Topical tetracycline compositions

ABSTRACT

A topical therapeutic hydrophobic breakable composition includes a carrier comprising (a) about 60% to about 99% by weight of at least one hydrophobic oil; (b) at least one viscosity-modifying agents selected from the group consisting of a fatty alcohol, a fatty acid and a wax; and (c) a tetracycline antibiotic, characterized in that at least part of the tetracycline antibiotic is suspended in the composition; the viscosity of the composition is at least about 30% higher than the viscosity of the carrier without the tetracycline antibiotic; and is higher than the viscosity or the hydrophobic oil and the tetracycline antibiotic without the viscosity modifying agents. The tetracycline is chemically stable in the composition for at least six months; wherein more than about 90% of the tetracycline has not broken down. The composition is packaged as a breakable foam that breaks easily upon application of shear force.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/235,964, filed Dec. 28, 2018, which is a continuation of U.S.application Ser. No. 15/591,733, filed May 10, 2017; which is acontinuation of U.S. application Ser. No. 14/595,882, filed Jan. 13,2015; which is a continuation of U.S. application Ser. No. 14/469,792,filed Aug. 27, 2014; which is a continuation of U.S. application Ser.No. 14/327,040, filed Jul. 9, 2014; which is a continuation of U.S.application Ser. No. 13/499,475, filed Sep. 14, 2012; which is a U.S.National Stage entry under 35 U.S.C. § 371 of International ApplicationNo. PCT/IB2010/002617, filed Oct. 1, 2010; which claims the benefit ofpriority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.61/388,884 filed Oct. 1, 2010; U.S. Provisional Application No.61/248,144 filed Oct. 2, 2009 and entitled “Surfactant-Free Water-FreeFoamable Compositions, Breakable Foams and Their Uses”; U.S. ProvisionalApplication No. 61/322,148 filed Apr. 8, 2010 and entitled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams andTheir Uses”; U.S. Provisional Application No. 61/349,911 filed May 31,2010 and entitled “Surfactant-Free Water-Free Foamable Compositions,Breakable Foams and Their Uses”; U.S. Provisional Application No.61/385,385 filed Sep. 22, 2010 and entitled “Surfactant-Free Water-FreeFoamable Compositions, Breakable Foams and Gels and Their Uses”; U.S.Provisional Application No. 61/331,126 filed May 4, 2010 and entitled“Compositions, Gels and Foams with Rheology Modulators and UsesThereof”; and U.S. Provisional Application No. 61/380,568 filed Sep. 7,2010 and entitled “Surfactant-Free Water-Free Foamable Compositions andBreakable Foams and Their Uses”; all of which are herein incorporated intheir entirety by reference.

BACKGROUND

Tetracyclines are broad-spectrum antibiotic, which are routinely usedorally for the treatment of dermatological conditions, such as acne androsacea. However, despite their high therapeutic value, tetracyclinesare very unstable, and they are known to be incompatible with manyformulation excipients, including water, various protic substances andoxidizing agents.

Topical tetracycline was the first topical antibiotic approved for thetreatment of acne, its use has been limited because of the skinpenetration problems of the active ingredient (Adişen E et al, “Topicaltetracycline in the treatment of acne vulgaris”, J Drugs Dermatol. 2008;7:953-5). The vehicle of this product is an ointment base, comprisingpetrolatum (which is greasy and unusable in the case of facial treatmentof acne and rosacea).

Tetracycline hydrophobic compositions intended to be mixed with anexternal source of protic liquid are known. They comprise a hydrophobicnon-hygroscopic silicone thickening agent, preferably a siliconeelastomer, in concentrations of more than 5%. This mixing results insubstantial solubilization of the tetracycline, thus rendering it“suitable for topical delivery. Such a product, which requires mixingtwo components prior to administration by the patient is cumbersome andhas no or little practical or viable value; and furthermore, it woulddegrade and form degradation products if left for a while prior totreatment.

SUMMARY

The present application relates to oleaginous gel formulations, foamableformulations and foams comprising tetracycline, which are stable andtheir therapeutic uses.

The application also relates to foamable formulations and foam withoutsurfactants; and or without surfactants and polymeric agents. In one ormore embodiments the hydrophobic solvents are provided as part of a drugcarrier. For example certain drugs require hydrophobic solvents in orderto solubilize them.

In one or more other embodiments, the hydrophobic solvents are providedto facilitate or enhance the intradermal penetration or delivery of adrug. In one or more additional cases, the hydrophobic solvents areprovided to have an occlusive effect at the target site, for examplewhere the site of treatment is a damaged skin and the occlusive effectof hydrophobic solvents is desirable. The present application furtherrelates to compositions comprising hydrophobic solvents and their uses.The application further describes semi solid gel compositions thatliquefy on application of mild shear force such as gentle rubbing.

In one or more embodiments there is provided topical therapeutichydrophobic breakable composition comprising

-   -   a. a carrier comprising        -   i. about 60% to about 99% by weight of at least one            hydrophobic oil        -   ii. at least two viscosity-modifying agents selected from            the group consisting of a fatty alcohol, a fatty acid and a            wax    -   b. a tetracycline antibiotic    -   characterized in that    -   (i) at least part of the tetracycline antibiotic is suspended in        the composition;    -   (ii) the viscosity of the composition is at least about 30%        higher than the viscosity of the carrier without the        tetracycline antibiotic; and is higher than the viscosity of the        hydrophobic oil and the tetracycline antibiotic without the        viscosity modifying agents;    -   (iii) the amount of viscosity modifying agents can optionally be        reduced by at least an amount by weight that would have        increased the viscosity of the carrier without the tetracycline        antibiotic by at least 30%;    -   wherein the tetracycline is chemically stable in the composition        for at least six months    -   wherein more than about 90% of the tetracycline has not broken        down;        wherein when packaged in an aerosol container to which is added        a liquefied or compressed gas propellant the composition affords        upon release from the container a breakable foam of at least        good quality that breaks easily upon application of shear force.

It is known in the art that foams can easily be formulated based on highamounts of water, in combination with surface active agents, foamadjuvants and polymeric agents. As described in the literature,hydrophobic solvents can have a de-foaming effect which makes theformulation of foams based on hydrophobic solvents—challenging. Toovercome this challenge, the prior art requires the use of substantiallevels of surfactants that act as foaming agents. Surface active agentsare known to be irritating, especially ionic surface active agents andrepeated use can cause dry skin and so it is desirable to reduce theiruse in pharmaceutical compositions intended to treat skin or mucosa. Theprior art further teaches the incorporation of foam adjuvants, such asfatty alcohols and fatty acids, as foam boosting agents and also theincorporation of polymeric agents (e.g. gelling agents) as foamstabilizers, which can prolong the collapse time of a foam. Waxes mayalso be introduced into these surfactant based formulations but as willbe appreciated, waxes, which are solids at ambient temperature, caneasily precipitate.

The technical problems to be overcome in formulating oleaginous carriersand pharmaceutical compositions with hydrophobic solvent (a) withoutsurfactants; and/or (b) without polymeric agents and/or (c) withoutwater and/or (e) without short chain alcohols and/or (f) withoutpolyols; are multifold and include finding a suitable substitute forsurfactant which provides foam generating properties; finding a suitablereplacement that preferably does not need to have a foam adjuvantpresent with the surfactant (substitute), which if present would interalia help to boost the foam and as an aid to the surfactant andpreferably does not need to have a polymeric agent present with thesurfactant (substitute), which if present would inter alia help prolongstability of the foam.

It was surprisingly discovered in the present invention, that surfaceactive agents can be advantageously eliminated and replaced byviscosity-modifying agents consisting of a fatty alcohol, a fatty acidand a wax in the context of hydrophobic solvent based-foams. Waxespossess several advantages over other foaming agents such as excellentskin compatibility, almost no chemical reactivity which ensures activeingredients stability and efficient skin occlusion which helps reducingskin water loss and can enhance skin penetration of active agents.Albeit waxes introduce their own additional problems into formulatingfoamable compositions and foams, including their tendency to solidifyand precipitate out from a formulation and to block canister valves,against which the formulations need to be designed so that theformulations are not negatively disturbed upon adding an effectiveamount of propellant and that the formulations are shakable and arehomogenous and can readily reform at least upon mild or reasonableshaking prior to use.

Another challenge is how to adjust the rheology as primarily expressedin the viscosity of the formulation before and after adding propellantso that before it can exhibit gel like properties and that afteraddition it is shakable in the canister, Additionally the compositionshould be capable of generating a foam that when applied to a target isneither a liquid nor very viscous but is comfortable an convenient forapplication. Further, costs of toxicology and trials may besubstantially reduced where the gel and the foam are capable of showingequivalency for pharmaceutical purposes.

Incorporated in or added to the above is the aspect of how to provideformulations in which unstable active ingredients, such astetracyclines, which readily degrade can nevertheless remainsufficiently chemically stable for prolonged periods of time such thatallowing for a reasonable or acceptable amount of breakdown (for exampleas may be accepted by a regulatory drug authority) they remain capableof providing a therapeutic effect or prevention or remission of adisorder or disease (hereinafter “chemically stable”). A furtherchallenge is providing and delivering a composition in which the activeagent is homogenous, especially when the active agent is not dissolved.Additionally the formulations should avoid the use of substances, whichcan be irritating if applied to a sensitive target or can causedepletion or drying or soreness on repeated use.

Incorporated in or added to the above is the aspect of how to providephysically stable formulations which are at least short term stable uponrelease from the pressurized container and not break as a result ofexposure to skin temperature. Foams which are structurally stable on theskin for at least one minute are termed “short term stable”. In anotheraspect of physically stability the foamable formulation includingpropellant remains homogenous and does not separate to any significantextent for at least one minute after being shaken (hereinafter“physically stable”).

In one aspect, a topical therapeutic hydrophobic breakable compositionincludes a carrier comprising about 60% to about 99% by weight of atleast one hydrophobic oil and at least one viscosity-modifying agentsselected from the group consisting of a fatty alcohol, a fatty acid anda wax; and a tetracycline antibiotic, characterized in that at leastpart of the tetracycline antibiotic is suspended in the composition andthe viscosity of the composition is at least about 30% higher than theviscosity of the carrier without the tetracycline antibiotic; and ishigher than the viscosity of the hydrophobic oil and the tetracyclineantibiotic without the viscosity modifying agents; and wherein afterstorage at 25° C. for at least two months the composition retains atleast 90% of the tetracycline initially present in the composition; andwherein when packaged in an aerosol container to which is added aliquefied or compressed gas propellant the composition affords uponrelease from the container a breakable foam of at least good qualitythat breaks easily upon application of shear force.

In one or more embodiments, the tetracycline at least 95% or at least97% of the tetracycline initially present is present after at least twomonths.

In one or more embodiments, the tetracycline at least 90% or at least95% or at least 97% of the tetracycline initially present is presentafter at least three months.

In one or more embodiments, the tetracycline at least 90% or at least95% or at least 97% of the tetracycline initially present is presentafter at least six months.

In one or more embodiments, the amount of tetracycline present isdetermined by HPLC.

In one or more embodiments, the increase in viscosity is a synergisticincrease such that the combined viscosity of the carrier and theviscosity of the hydrophobic oil and the tetracycline antibiotic is lessthan the viscosity of the composition.

In one or more embodiments, the hydrophobic breakable vehicle is in theform of a gel prior to addition of propellant; wherein said gelliquefies and spreads easily upon application of mild shear force.

In one or more embodiments, the hydrophobic breakable vehicle is in theform of a foam; wherein said foam has a collapse time of greater thanabout 3 minutes.

In one or more embodiments, the ratio of composition other thanpropellant to propellant is from about 100:1 to about 100:25.

In one or more embodiments, the at least one hydrophobic oil is selectedfrom the group consisting of a mineral oil, a hydrocarbon oil, an esteroil, an ester of a dicarboxylic acid, a triglyceride oil, an oil ofplant origin, an oil from animal origin, an unsaturated orpolyunsaturated oil, a diglyceride, a PPG alkyl ether, an essential oil,a silicone oil, liquid paraffin, an isoparaffin, a polyalphaolefin, apolyolefin, polyisobutylene, a synthetic isoalkane, isohexadecane,isododecane, alkyl benzoate, alkyl octanoate, C12-C15 alkyl benzoate,C12-C15 alkyl octanoate, arachidyl behenate, arachidyl propionate,benzyl laurate, benzyl myristate, benzyl palmitate, bis (octyldodecylstearoyl) dimer dilinoleate, butyl myristate, butyl stearate, cetearylethylhexanoate, cetearyl isononanoate, cetyl acetate, cetylethylhexanoate, cetyl lactate, cetyl myristate, cetyl octanoate, cetylpalmitate, cetyl ricinoleate, decyl oleate, diethyleneglycoldiethylhexanoate, diethyleneglycol dioctanoate, diethyleneglycoldiisononanoate, diethyleneglycol diisononanoate, diethylhexanoate,diethylhexyl adipate, diethylhexyl malate, diethylhexyl succinate,diisopropyl adipate, diisopropyl dimerate, diisopropyl sebacate,diisosteary dimer dilinoleate, diisostearyl fumerate, dioctyl malate,dioctyl sebacate, dodecyl oleate, ethylhexyl palmitate, esterderivatives of lanolic acid, ethylhexyl cocoate, ethylhexylethylhexanoate, ethylhexyl hydroxystarate, ethylhexyl isononanoate,ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexyl stearate,hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetyl isocetylbehenate, isocetyl lanolate, isocetyl palmitate, isocetyl stearate,isocetyl salicylate, isocetyl stearate, isocetyl stearoyl stearate,isocetearyl octanoate, isodecyl ethylhexanoate, isodecyl isononanoate,isodecyl oleate, isononyl isononanoate, isodecyl oleate, isohexyldecanoate, isononyl octanoate, isopropyl isostearate, isopropyllanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate,isopropyl stearate, isostearyl behenate, isosteary citrate, isostcarylerucate, isostcaryl glycolate, isostcaryl isononanoate, isostcarylisostearate, isostearyl lactate, isostearyl linoleate, isostearyllinolenate, isostearyl malate, isostearyl neopentanoate, isostearylpalmitate, isosteary salicylate, isosteary tartarate, isotridecylisononanoate, isotridecyl isononanoate, lauryl lactate, myristyllactate, myristyl myristate, myristyl neopentanoate, myristylpropionate, octyldodecyl myristate, neopentylglycol dicaprate, octyldodecanol, octyl stearate, octyl palmitate, octyldodecyl behenate,octyldodecyl hydroxystearate, octyldodecyl myristate, octyldodecylstearoyl stearate, oleyl erucate, oleyl lactate, oleyl oleate, propylmyristate, propylene glycol myristyl ether acetate, propylene glycoldicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate,maleated soybean oil, stearyl caprate, stearyl heptanoate, stearylpropionate, tocopheryl acetate, tocopheryl linoleate, glyceryl oleate,tridecyl ethylhexanoate, tridecyl isononanoate, triisocetyl citrate,alexandria laurel tree oil, avocado oil, apricot stone oil, barley oil,borage seed oil, calendula oil, canelle nut tree oil, canola oil,caprylic/capric triglyceride castor oil, coconut oil, corn oil, cottonoil, cottonseed oil, evening primrose oil, flaxseed oil, groundnut oil,hazelnut oil, glycereth triacetate, glycerol triheptanoate, glyceryltrioctanoate, glyceryl triundecanoate, hempseed oil, jojoba oil, lucerneoil, maize germ oil, marrow oil, millet oil, neopentylglycoldicaprylate/dicaprate, olive oil, palm oil, passionflower oil,pentaerythrityl tetrastearate, poppy oil, propylene glycol ricinoleate,rapeseed oil, rye oil, safflower oil, sesame oil, shea butter, soya oil,soybean oil, sweet almond oil, sunflower oil, sysymbrium oil, syzigiumaromaticum oil, tea tree oil, walnut oil, wheat germ glycerides, wheatgerm oil, PPG-2 butyl ether, PPG-4 butyl ether, PPG-5 butyl ether, PPG-9butyl ether, PPG-12 butyl ether, PPG-14 butyl ether, PPG-15 butyl ether,PPG-15 stearyl ether, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18butyl ether, PPG-20 butyl ether, PPG-22 butyl ether, PPG-24 butyl ether,PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butylether, PPG-52 butyl ether, PPG-53 butyl ether. PPG-10 cetyl ether,PPG-28 cetyl ether, PPG-30 cetyl ether, PPG-50 cetyl ether, PPG-30isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether, PPG-2 methylether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG-4 myristyl ether,PPG-10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleyl ether, PPG-30 oleylether, PPG-37 oleyl ether, PPG-40 butyl ether, PPG-50 oleyl ether,PPG-11 stearyl ether, herring oil, cod-liver oil, salmon oil,cyclomethicone, a dimethyl polysiloxane, dimethicone, an epoxy-modifiedsilicone oil, a fatty acid-modified silicone oil, a fluorogroup-modified silicone oil, a methylphenylpolysiloxane, phenyltrimethicone and a polyether group-modified silicone oil.

In one or more embodiments, the fatty alcohol has at least 12 carbonatoms in its carbon backbone; and wherein said fatty acid has at least12 carbon atoms in its carbon backbone.

In one or more embodiments, the fatty alcohol and said fatty acid have amelting point of more than about 40° C.

In one or more embodiments, the fatty alcohol is selected from the groupconsisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearylalcohol, arachidyl alcohol, behenyl alcohol, tetracosanol, hexacosanol,octacosanol, triacontanol, tetratriacontanol; and wherein said fattyacid is selected from the group consisting of dodecanoic acid,tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoicacid, eicosanoic acid, docosanoic acid, tetracosanoic acid, hexacosanoicacid, heptacosanoic acid, octacosanoic acid, triacontanoic acid,dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid andpentatriacontanoic acid.

In one or more embodiments, the carbon chain of said fatty alcohol orsaid fatty acid is substituted with a hydroxyl group, and for example,the carbon chain of said fatty acid is 12-hydroxy stearic acid.

In one or more embodiments, wax is selected from the group consisting ofa plant wax, carnauba wax, candelilla wax, ouricury wax, sugarcane wax,retamo wax, jojoba oil, an animal waxes, beeswax, a petroleum derivedwax, a paraffin wax, polyethylene and derivatives thereof.

In one or more embodiments, the viscosity-modifying agent is acombination comprising (i) at least one fatty alcohol and at least onefatty acid; or (ii) at least one fatty alcohol and least one wax; or(iii) at least one fatty acid and at least one wax; or (iv) at least onefatty alcohol, at least one fatty acid and least one wax.

In one or more embodiments, the hydrophobic breakable vehicle issubstantially free of surface active agents, protic solvents, polaraprotic solvents and silicone thickening agents.

In one or more embodiments, the hydrophobic breakable vehicle issubstantially free of surface active agents, polymeric gelling agents,polyols, short chain alcohols and silicone thickening agents.

In one or more embodiments, the hydrophobic breakable vehicle containsless than about 0.4%; or less than about 0.2%; or less than about 0.1%of surface active agents, protic solvents, polar aprotic solvents andsilicone thickening agents.

In one or more embodiments, the tetracycline antibiotic is selected fromthe group consisting of tetracycline, oxytetracycline, demeclocycline,doxycycline, lymecycline, meclocycline, methacycline, minocycline,rolitetracycline, chlorotetracycline and tigecycline, and for example,the tetracycline antibiotic is hydrophobic.

In one or more embodiments, the tetracycline antibiotic is present in afree base form a hydrate form, a salt form or a complex form, and forexample, the Log of the distribution constant of the tetracyclineantibiotic at pH 7.0 (buffer/chloroform) is equal to or less than about0.2.

In one or more embodiments, the tetracycline antibiotic does notcomprise any hydroxy group at Carbons 5, 6, and 7, and for example, thetetracycline antibiotic is selected from the group of minocycline anddoxycycline; or is minocycline.

In one or more embodiments, the composition further comprises anadditional active agent.

In one or more embodiments, the additional active agent is selected formthe group consisting of an active herbal extract, an acaricides, an agespot and keratose removing agent, an allergen, an alpha hydroxyl acid,an analgesic agent, an androgen, an antiacne agent, an antiallergicagent, an antiaging agent, an antibacterial agent, an antibiotic, anantiburn agent, an anticancer agent, an antidandruff agent, anantidepressant, an antidermatitis agent, an antiedemic anent, anantifungal agent, an antihistamine, an antihelminth agent, ananti-hyperkeratosis agent, an anti-infective agent, an antiinflammatoryagent, an antiirritant, an antilipemic agent, an antimicrobial agent, anantimycotic agent, an antioxidant, an antiparasitic agent, anantiproliferative agent, an antipruritic agent, an antipsoriatic agent,an antirosacea agent, an anti eborrheic agent, an antiseptic agent, anantiswelling agent, an antiviral agent, an anti-wart agent, ananti-wrinkle agent, an antiyeast agents, an astringent, a beta-hydroxyacid, benzoyl peroxide, a topical cardiovascular agent, achemotherapeutic agent, a corticosteroid, an immunogenic substance, adicarboxylic acid, a disinfectant, an estrogen, a fungicide, a hairgrowth regulator, a haptene, a hormone, a hydroxy acid, animmunosuppressant, an immunoregulating agent, an immunomodulator, animmunostimulant, an insecticide, an insect repellent, a keratolyticagent, a lactam, a local anesthetic agent, a lubricating agent, amasking agent, a metals, a metal oxide, a mitocide, a neuropeptide, anon-steroidal anti-inflammatory agent, an oxidizing agent, apediculicide, a peptide, a pesticide, a protein, a photodynamic therapyagent, a progesterone, a radical scavenger, a refatting agent, aretinoid, a sanative, a scabicide, a sedative, a self tanning agent, askin protective agent, a skin whitening agent, a steroid, a steroidhormone, a vasoactive agent, a vasoconstrictor, a vasodilator, avitamin, a vitamin A, a vitamin A derivative, a vitamin B, a vitamin Bderivative, a vitamin C, a vitamin C derivative, a vitamin D, a vitaminD derivative, a vitamin D analog, a vitamin F, a vitamin F derivative, avitamin K, a vitamin K derivative, a wound healing agent and a wartremover.

In one or more embodiments, wherein, when tested in the Franz-cell invitro model using human or pig's skin, affords an amount of thetetracycline in the skin which is higher than the respective amounttransferred transdermally.

In one or more embodiments, wherein, when tested in the Franz-cell invitro model using human or pig's skin, the ratio between the amount ofthe tetracycline in the skin and the respective amount transferredtransdermally is higher than about 100:1; or between about 100:1 andabout 10:1; or between about 10:1 and about 2:1; or more than 1:1.

In one or more embodiments, wherein the concentration of thetetracycline in the hydrophobic breakable composition is higher than thelowest concentration which results in intradermal delivery of sufficientconcentrations of the tetracycline to have a therapeutic effect whentested in the Franz-cell in vitro model, using human or pig's skin.

In one or more embodiments, wherein the composition prevents thedegradation of the tetracycline antibiotic upon application on thetarget site of treatment.

In another aspect, a method of preventing, treating or alleviating thesymptoms of a dermatological, an opthalmological, a gynecologic ormucosal disorder includes applying topically to the target area ahydrophobic therapeutic composition as described herein.

In one or more embodiments, the disorder includes bacterial infection,inflammation, oxidative stress, and neurodgeneration and/or apoptosis asone of it etiological factors.

In one or more embodiments, the disorder is selected from the groupconsisting of a dermatological condition abscess, acne, acne conglobata,acne fulminans, acne vulgaris, acne scars, acute febrile neutrophilicdermatosis, acute lymphangitis, allergic contact dermatitis, alopecia,athlete's foot, atopic dermatitis, bacterial skin infections, baldness,basal cell carcinoma, blisters, bromhidrosis, bullous pemphigoid, burn,calluses candidiasis, carbuncles, cellulitis, chemical burns, chickenpox, cholesteatoma, cholinergic urticaria, chronic effects of sunlight,cold sores, cold urticaria, comedones, corns, creeping eruption,cutaneous abscess, cutaneous larva migrans, cutaneous myiasis, darkspots, delusional parasitosis, Dercum disease, dermatitis, dermatitisherpetiformis, dermatological pain, dermatological inflammation,dermographism, dermatophytoses, drug eruptions and reactions,dyshidrotic eczema, ectodermal dysplasia, eczema, ecthyma, epidermoidcyst, epidermal necrolysis, erysipelas, erysipelas, erythrasma,exfoliative dermatitis, erythema multiforme, erythema nodosum,folliculitis, fungal nail infections, fungal skin infections, furuncles,gangrene, genital herpes, granuloma annulare, head lice, hidradenitissuppurativa, hives, folliculitis, hirsutism, hyperhidrosis,hypohidrosis, ichthyosis, impetigo, inflammatory acne, ingrown nails,intertrigo, irritant contact dermatitis, ischemic necrosis, itching,jock itch, Kaposi's sarcoma, keratosis pilaris, lichen simplexchronicus, lichen planus, lichen sclerosus, lymphadenitis,lymphadenitis, lymphangitis, malignant melanoma, mastocytosis, measles,melanoma, melanoma, miliaria, moles, molluscum contagiosum, MRSA,necrotizing subcutaneous infection, necrotizing fasciitis, necrotizingmyositis, nodular papulopustular acne, non-inflammatory acne, nummulardermatitis, oral herpes, panniculitis, parapsoriasis paronychia,parasitic skin infections, pemphigus, photo-allergy, photo-damage,photo-irritation, photosensitivity, papules, pediculosis, perioraldermatitis, pimples, pityriasis rosea, pityriasis Lichenoides,pityriasis rosea, pityriasis rubra pilaris, poison ivy, post-operativeor post-surgical skin conditions, pressure ulcers, pressure urticaria,pruritis, pseudofolliculitis barbae, psoriasis, PUPPP, purpura,pustules, pyogenic granuloma, rash, ringworm, rosacea, roseola, rubella,scabies, scalded skin syndrome, scarring, scleroderma, sebaceous cyst,seborrheic dermatitis, seborrheic keratosis, shingles, skin aging, skincancer, skin neoplasia, skin neoplasms, skin rash, skin ulcers, squamouscell carcinoma, staphylococcal scalded skin syndrome, stasis dermatitis,Stevens-Johnson syndrome, sunburn, sun spots, thermal burns, tineacorporis, tinea cruris, tinea pedis, tinea versicolor, toxic epidermalnecrolysis, trauma or injury to the skin, varicella zoster virus,vitamin D deficiency, viral skin infections, vitiligo, warts, waterhives, wrinkles, xerosis, yeast skin infections and zoster; a disorderof a body cavity or mucosal surface, a disorder of the nose, mouth, eye,ear, respiratory system, vagina, urethra, or rectum, chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chaneroid, granuloma Inguinale, lymphogranloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum; anophthalmic disorder, eye redness, eye pain or light sensitivity, blurredvision, loss of vision, visual disturbances—floaters, flashing,distortion, halos, etc., itching/burning, tearing/discharge, sensationof something in the eye, eyelid problems, double vision; ophtahlmicallergy, blepharitis, cataract, central serous chorioretinopathy, colorvision problems, corneal abrasion, corneal edema, corneal ulcer,conjunctivitis, contact lens complications, dacryocystitis, blurreddistance vision, dry eye, eale's disease, episcleritis, eyelidectropion, eyelid entropion, eyelid cellulitis, eye strain, focusingspasm, glaucoma, acute glaucoma, iritis, keratoconus, lyme disease,macular degeneration, macular edema, macular hole, eye medicationtoxicity, myasthenia gravis, ocular cicatricial pemphigoid, ophthalmicmigraine, presbyopia, obstructed tear duct, optic neuritis, optic nervestroke, orbital fracture, orbital cellulitis, phlyctenulosis, pterygium,recurrent corneal erosion, retinal artery occlusion, retinal detachment,retinal tear, retinal vein occlusion, sarcoidosis, scleritis, sinusdisease, strabismus (ocular misalignment), subconjunctival hemorrhage,temporal arteritis, thyroid eye disease, trichiasis, eyelid tumor,twitching of eyelid (eyelid myokymia), uveitis, vitreous detachment andvitreous hemorrhage.

In one or more embodiments, the disorder is selected from the groupconsisting of a skin infection, acne, rosacea, an eye infection, ocularrosacea, blepharitis, dry eye, trachoma and glaucoma.

In one or more other specific embodiments the drug carrier is formulatedsubstantially free of elastomers. In one or more other specificembodiments the drug carrier is formulated essentially free ofelastomers. In one or more other specific embodiments the drug carrieris formulated substantially free of silicones. In one or more otherspecific embodiments the drug carrier is formulated essentially free ofsilicones. In one or more other specific embodiments the drug carrier isformulated with less than about 30% silicone, or less than about 25%silicone, or less than about 20% silicone, or less than about 15%silicone, or less than about 10% silicone, or less than about 7.5%silicone, or less than about 5% silicone or less than about 2% silicone;or less than about 1% silicone; or less than about 0.5% silicone.

DETAILED DESCRIPTION

The present invention is directed to a hydrophobic breakabletetracycline formulation for topical administration, wherein theformulation is (i) in the form of an oil gel that liquefies and spreadseasily upon application of mild shear force; or (ii) an oil foam;wherein said oil foam is stable upon dispensing from the aerosol can andbreaks down and spreads easily upon application of mild shear force.

The formulation of the invention is suitable for topical administrationto the skin and mucosal membranes, the eyes, nasal cavity, the ear canaland the vaginal cavity.

A feature of a product for medical use is long term stability. Thecompositions herein are surprisingly stable. Following acceleratedstability studies, they demonstrate desirable texture, do not breakimmediately upon contact with a surface, spread easily on the treatedarea and absorb quickly.

In one or more embodiments the composition has an acceptable shelf-lifeof at least six months. In one or more embodiments the foam compositionhas an acceptable shelf-life of at least one year, In one or moreembodiments the foam composition has an acceptable shelf-life of atleast 15 months, or at least 18 months or at least 21 months or at leasttwo years at ambient temperature.

In one or embodiments stability is inter alia a product of extensiveeffort and research; eliminating surfactants; eliminating water; choiceof components; testing each component individually with the active agent(compatibility studies); the combination of components, having anappropriate Aw value (e.g. <9), storage in an air and light tightcontainer.

In one or more embodiments the active agent is considered chemicallystable when more than about 90% of the active agent does not break downafter a period of two months in the formulation at room temperature. Inone or more embodiments the period is six months. In one or moreembodiments more than about 88% of the active agent does not break down.In one or more embodiments the active agent is chemically stable in thecomposition at 40° C.

In one or more embodiments the drug carrier is formulated substantiallyfree of short chain alcohols, such as, ethanol, propanol or butanol. Inone or more embodiments the drug carrier is formulated essentially freeof short chain alcohols. In one or more specific embodiments the drugcarrier is formulated essentially free of derivatives of fatty alcoholsor fatty acids. In one or more other specific embodiments the drugcarrier is formulated essentially free of polyols. In one or more otherspecific embodiments the drug carrier is formulated substantially freeof surfactants and or short chain alcohols and or polyols. In one ormore other specific embodiments the drug carrier is formulatedessentially free of surfactants and or short chain alcohols and orpolyols. In one or more embodiments there is provided a compositionwhich is essentially waterless. In one or more embodiments there isprovided a surfactant free composition that is also free of short chainalcohols and or polyol-free. In one or more embodiments there isprovided a substantially polymer free composition. In other embodimentsit is essentially polymer free. In still further embodiments thecomposition is free of polymeric agent. In one or more embodiments apolymeric agent has a Molecular weight of at least about 1000 Daltons.

In one or more embodiments the composition is essentially free of two ormore of water; polymeric agent; surfactant; short chain alcohol; orpolyol. In one or more embodiments the composition is essentially freeof three or more of water; polymeric agent; surfactant; short chainalcohol; or polyol. In one or more embodiments the composition isessentially free of four or more of water; polymeric agent; surfactant;short chain alcohol; or polyol. In one or more embodiments thecomposition is essentially free of water, polymeric agent; surfactant;short chain alcohol; and polyol.

In one or more other specific embodiments the drug carrier is formulatedsubstantially free of elastomers. In one or more other specificembodiments the drug carrier is formulated essentially free ofelastomers. In one or more other specific embodiments the drug carrieris formulated substantially free of silicones. In one or more otherspecific embodiments the drug carrier is formulated essentially free ofsilicones. In one or more other specific embodiments the drug carrier isformulated with less than about 30% silicone, or less than about 25%silicone, or less than about 20% silicone, or less than about 15%silicone, or less than about 10% silicone, or less than about 7.5%silicone, or less than about 5% silicone or less than about 2% silicone;or less than about 1% silicone; or less than about 0.5% silicone.

Definitions

All % values are provided on a weight (w/w) basis.

In one or more embodiments wherever a phrase is used to refer to aconcentration of above X % or below X % it can also include X % or aboveabout X % or below about X % it can also include about X %.

In one or more embodiments the term “about” has its usual meaning in thecontext of pharmaceutical and cosmetic formulations to allow forreasonable variations in amounts that can achieve the same effect. Bythe term “about” herein it is meant as indicated above and also that afigure or range of figures can vary in an embodiments plus or minus upto 30%. So in this embodiment if a figure of “about 1” is provided thenthe amount can be up to 1.3 or from 0.70. In other embodiments it canreflect a variation of plus or minus 20%. In still further embodimentsit can describe a variation of plus or minus 10%. In still furtherembodiments it can describe a variation of plus or minus 5%. As will beappreciated by one of the art there is some reasonable flexibility informulating compositions such that where one or more ingredients arevaried successful formulations may still be made even if an amount fallsslightly outside the range. Therefore, to allow for this possibilityamounts are qualified by about. In one or more other embodiments thefigures may be read without the prefix about.

The term “thixotropic,” as used herein, means that the formulation showsa significant decrease in viscosity upon application of shear force.

The term “waterless,” as used herein, means that the compositioncontains no, or substantially no, free or unassociated or absorbedwater. Similarly, “waterless” or “substantially waterless” carrierscontain at most incidental and trace amounts of water.

By the term “single phase” herein it is meant that the liquid componentsof the composition or carrier are fully miscible, and the solidcomponents if any, are either dissolved or suspended in the composition.By substantially a single phase is meant that the composition or carrieris primarily or essentially a single phase as explained above, but mayalso have present a small amount of material which is capable of formingor may form a separate phase amounting to less than about 5% of thecomposition or carrier, preferably less than about 3%, and morepreferably less than about 1%. By the term “single phase” or“substantially a single phase” in the context of a foamable compositionthe above meaning applies even after addition of propellant to thecomposition or carrier.

The term “unstable active agent” as used herein, means an active agentwhich is oxidized and/or degraded within less than a day, and in somecases, in less than an hour upon exposure to air, light, skin or waterunder ambient conditions.

The term “co-surfactant” as used herein, means a compound which on itsown is not able to form and stabilize satisfactorily an oil in wateremulsion, but when used in combination with a surfactant, suchco-surfactant can boost the emulsifying power of surfactants to create astable emulsion. For example, fatty alcohols, such as cetyl alcohol or afatty acid such as stearic acid can function as co-surfactants. Cetylalcohol and stearyl alcohol are waxy hydrophobic substances that can beemulsified with water using a surfactant. In certain circumstances aco-surfactant can itself be converted in to a surfactant or soap by, forexample, adding a base, such as, triethanolamine to a fatty acid,resulting in a fatty acid salt, which is also termed “soap” (a stronganionic surfactant).

The identification of a “polyol”, as used herein, is an organicsubstance that contains at least two hydroxy groups in its molecularstructure.

Gel and Foam Presentations

The topical therapeutic hydrophobic breakable composition of the presentinvention can be presented as a gel or as a foam. The term “breakable”,as used herein relates to a composition is stable as a gel or as a foamupon dispensing from a container, yet breaks and spreads easily uponapplication of mild shear force.

It was surprisingly discovered in the present invention, that certaincompositions comprising a hydrophobic solvent, together withviscosity-modifying agents which may be at least one fatty alcoholand/or at least one fatty acid, and/or at least one wax and mixtures oftwo or more thereof; and a suspended active agent; without any surfaceactive agents afford, upon packaging in an aerosol container and addinga propellant, a shakable and homogenous foamable composition, whichreleases a breakable foam with good to excellent quality (as definedherein.

The resulting foam is pharmaceutically equivalent to the respective gel(prior to adding the propellant), since immediately upon dispensing ofthe foam the propellant evaporates and the composition uponadministration is similar to that of the gel. This is an importantpragmatic advantage, because many drug development activities, includingexpensive and lengthy toxicology studies with numerous animals andclinical trials with thousands of patients can be saved by conductingsuch studies once for the gel and foam presentation instead of twice(for each presentation).

Gel

The primary essential components the gel of the present inventioncomprises (a) at least one hydrophobic oil, (b) at least oneviscosity-modifying agent and (c) a tetracycline antibiotic. Theconcentration of the hydrophobic oil is between about 60% and about 99%by weight. In one or more other embodiments the concentration is betweenabout 60% and about 95%, or is between about 65% and about 99%, or isbetween about 65% and about 95%, or is between about 70% and about 95%,or is between about 75% and about 95%, or is between about 80% and about95%, or is between about 85% and about 99%, or is between about 85% andabout 95%.

Surprisingly, we discovered that, while the addition of theviscosity-modifying agents to the hydrophobic oil increased theviscosity of such oil, even small amounts of a suspended tetracyclineantibiotic increased the viscosity of the composition synergistically.The gel is stable and it retains its viscosity upon dispensing from acontainer, such as a tube, yet, it liquefies and spreads easily uponapplication of mild shear force. Further, whilst the gel is oily, itreadily absorbs into the site of application such as the skin, and aftera few minutes the surface looks and feels free of any oiliness orgreasiness.

The combination of a tetracycline with a mixture of one or morehydrophobic oils, fatty alcohols, fatty acids and waxes has a strongsynergistic effect and increases the formulation viscosity. For example,the viscosity of a formulation containing 0.50% minocycline HCl is aboutthree times higher than the viscosity of the same formulation withoutthe tetracycline. The effect on the formulation viscosity is directlyrelated to the concentration of the tetracycline: the higher thetetracycline concentration, the higher the viscosity of the formulation.In certain cases, it appeared that the viscosity increasing effect ofminocycline HCl reaches a plateau when the active ingredient is presentat a concentration of about 0.50% or, in certain embodiments, when theviscosity of the carrier is in excess of about 25,000 cps.

Thus, in one or more embodiments, there is provided a gel containing atleast one hydrophobic oil and a tetracycline in a synergisticcombination with a fatty alcohol, and/or a fatty acid and/or a wax,wherein the viscosity of the formulation is increased by the addition ofthe active ingredient by more than about 30%, or more than about 50%, ormore than about 100%, or more than about 200%, or more than about 300%,or more than about 500%.

In one or more embodiments, the increase in the formulation viscosity iscorrelated with the concentration of the active agent.

In one or more embodiments, the viscosity of the formulation is directlyproportional to the concentration of the active agent: the higher theconcentration of the active ingredient, the higher the formulationviscosity.

In one or more embodiments, the viscosity increasing effect of theactive ingredient reaches a plateau when the concentration of the activeingredient is increased.

In one or more embodiments, the viscosity of the formulation containingthe tetracycline is twice the viscosity of the sample formulation whenthe active ingredient is present at a concentration of less than about10%, less than about 5%, less than about 1%, less than about 0.5%, lessthan about 0.1%, less than about 0.05%, less than about 0.01%.

In one or more embodiments the viscosity of the gel is higher than about10000 cPs; or between about 1000 cPs and about 100000 cPs; or betweenabout 5000 cPs and about 50000 cPs; or between about 10000 cPs and about30000 cPs.

In one or more embodiments the increase in viscosity of the compositionis at least about 100% and viscosity of the carrier is less than about12,000 cPs; or less than about 8,000 cPs; or less than about 2,000 cPs.In one or more embodiments the viscosity of the carrier is more thanabout 1,000 cPs; or more than about 1,300 cPs; or more than about 1,500cPs. or more than about 1,800 cPs or more than about 2000 cPs. In one ormore embodiments the viscosity of the carrier is more than about 150cPs; or more than about 300 cPs, or more than about 500 cPs or more thanabout 800 cPs.

In one or more embodiments the change in viscosity is between about 50%and about 100%. In one or more embodiments the change in viscosity isbetween about 100% and about 500%. In one or more embodiments the changein viscosity is between about 500% and about 1000%. In one or moreembodiments the change in viscosity is between about 1000% and about1500%. In one or more embodiments the change in viscosity is betweenabout 1500% and about 2000%. In one or more embodiments the change inviscosity is between about 2000% and about 2500%. In one or moreembodiments the change in viscosity is between about 50% and about3000%. In one or more embodiments the change in viscosity is in a rangebetween about 150% and about 1000%. In one or more embodiments thechange in viscosity is in a range between about 1000% and about 2500% Inone or more embodiments the change in viscosity is between about 100%and about 2500%; about 100% and about 2000%; about 100% and about 1500%;or about 100% and about 1000%.

The gel composition has the unique property of stabilizing thetetracycline antibiotic and protecting it from degradation. For example,when a gel, containing about 83% hydrophobic oils, about 4.5% waxes,about 6% fatty alcohols and 5% fatty acid and about 1% micronizedminocycline HCl was applied to freshly retrieved and moist skin andstored on a Petri dish, with exposure to air and light for 6 hours theproduct remained substantially stable. Furthermore, even when a specimenof a hydrophobic gel with 1% minocycline was applied to a skin andexposed to direct sun light for two days, there was no apparentdegradation, as shown by the conservation of the skin color. Astetracycline antibiotics, and especially minocycline are know to besusceptible to degradation by air, water and light, this protectioneffect is unique.

In an additional observation, while the minocycline was protected fromthe environmental factors (moisture light and air), it is not hinderedor tightly encapsulated, as demonstrated by its efficient release intothe skin in an in-vitro Franz cell model, an antibacterial test modeland an anti-inflammation model, as further exemplified herein.

Foam

One skilled in the art would expect that a surfactant should be requiredin order to facilitate the production of foam.

However, surprisingly, when the gel composition described above,comprising (a) at least one hydrophobic oil, (b) at least oneviscosity-modifying agent, and (c) a tetracycline antibiotic isintroduced into an aerosol can, closed with an aerosol valve andpressurized with a propellant, it creates a breakable foam, i.e., a foamwhich is stable upon dispensing from a container, yet breaks and spreadseasily upon application of mild shear force. As in the case of the gel,the foam it readily absorbs into the site of application such as theskin, and after a few minutes the surface looks and feels free of anyoiliness or greasiness.

Foaming Propellant

Examples of suitable propellants include compressed gases, volatilehydrocarbons such as butane, propane, isobutane and fluorocarbon gases,or mixtures thereof.

In an embodiment, the propellant is hydrophobic and it miscible with theoils in the composition.

In certain embodiments, fluoro-hydrocarbon propellants, other thanchloro-fluoro carbons (CFCs) which are non-ozone-depleting propellants,are particularly useful in the production of a non-flammable foamablecomposition.

Such propellants include, but are not limited to hydrofluorocarbon (HFC)propellants, that contain no chlorine atoms, and as such, fallscompletely outside concerns about stratospheric ozone destruction bychlorofluorocarbons or other chlorinated hydrocarbons. Exemplarynon-flammable propellants according to this aspect of the inventioninclude propellants made by DuPont under the registered trademark Dymel,such as 1,1,1,2 tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3heptafluoropropane (Dymel 227), 1,1, difluoro ethane (Dymel 152) and1,1,1,3,3,3 hexafluoropropane. HFCs possess Ozone Depletion Potential of0.00 and thus, they are allowed for use as propellant in aerosolproducts.

Yet, in additional embodiments, the propellant is a self-foamingpropellant, i.e., a volatile liquid having a boiling point of less thanthe temperature of the target treatment site (such as the skin). Anexample of a post-foaming propellant is isopentane (bp=26° C.)

In an embodiment, the ratio of composition other than propellant topropellant is between about 100:1 to about 100:25, or is between about100:3 to about 100:30, or is between about 100:5 to about 100:20 or isbetween about 100:8 to about 100:16, or between about 100:20 and about100:50.

In one or more embodiments a foam formulation can be expelled or helpedto be expelled by using propellant which is separate from theformulation using, for example, a bag on valve (BOV) or can in canaerosol system. A BOV system consists of the aerosol valve with a weldedbag. With the BOV system compressed air or other propellants areintroduced in the aerosol can on the outside of the bag and acts as apropellant on the product which is inside the bag. Using such a systemmakes it possible to reduce the amount of propellant within theformulation but still enable expulsion from the canister of a foam withdesirable qualities. So by way of example, the concentration of thepropellant in the bag is between about 1% to 3%; or between about 2% to4%; between about 3% to 5% (ratio of formulation to propellant of 100:1to 100:3; 100:2 to 100:4; 100:3 to 5; respectively.

Foam Properties

A foamable composition manufactured according to one or more embodimentsherein is very easy to use. When applied onto the afflicted body surfaceof mammals, i.e., humans or animals, it is in a foam state, allowingfree application without spillage. Upon further application of amechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

In one or more embodiments the foamable composition is a single phasesolution. In one or more embodiments the foamable composition issubstantially a single phase solution. In certain circumstances, wherethe active agent is insoluble and is presented as a homogenoussuspension, the formulation is turbid or cloudy.

In one or more embodiments the foam composition has an acceptableshelf-life of at least one year, or at least two years at ambienttemperature. A feature of a product for cosmetic or medical use is longterm stability. Propellants, which are a mixture of low molecular weighthydrocarbons, or HFCs, tend to impair the stability. The foamablecompositions herein are surprisingly stable, even in the absence ofsurfactants. Following accelerated stability studies, they demonstratedesirable texture; they form fine bubble structures that do not breakimmediately upon contact with a surface. They spread easily on thetreated area and absorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam. Compositions containing a substantial amount ofsemi-solid hydrophobic oils, e.g., white petrolatum, as the mainingredients of the oil phase of the emulsion, will likely exhibit highviscosity and poor flowability and can be inappropriate candidates for afoamable composition. Thus in one or more embodiments semi-solidhydrophobic oils are a subsidiary component in the composition, forexample being present at less than about 25%, less than about 20%, lessthan about 15%, less than about 10%, or less than about 5% by weight ofthe foamable composition. In other embodiments they can be present inhigher amounts due to the solvent effect of the propellant diluting theformulation and enabling flowability or where the formulation ispresented as a gel or ointment or when solvents are added that reducethe viscosity such as alkyl benzoates.

Foam Quality

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof a more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

Foam Density

Another property of the foam is specific gravity or density, as measuredupon release from the aerosol can. Typically, foams have specificgravity of less than 0.5 g/mL; or less than 0.3 g/mL; or less than 0.2g/mL; or less than 0.1 g/mL, depending on their composition and on thepropellant concentration. In one or more embodiments the foam density isabout less than 0.3 g/mL.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. Shakability is describedfurther in the section on Tests. In one or more certain limitedembodiments the formulation is poorly shakable but is neverthelessflowable.

Breakability/Collapse Time

A further aspect of the foam is breakability. The balance betweenstability and breakability of the foam coming out of the container isvery delicate: on one hand the foam should preferably not be “quickbreaking”, i.e., it should be stable upon release from the pressurizedcontainer and not break as a result of exposure to skin temperature; andon the other hand, it should be “breakable”, i.e., it should spreadeasily, break down and absorb into the skin or membrane upon applicationof mild shear force. The breakable foam is thermally stable, yet breaksunder shear force. Shear-force breakability of the foam is clearlyadvantageous over thermally-induced breakability. Thermally sensitivefoams can start to collapse immediately upon exposure to skintemperature and, therefore, cannot be applied on the hand and afterwardsdelivered to the afflicted area.

The collapse time of foam represents its tendency to betemperature-sensitive and its ability to be at least stable in the shortterm so as to allow a user sufficient time to comfortably handle andapply the foam to a target area without being rushed and or concernedthat it may rapidly collapse, liquefy and or disappear. Collapse time,as an indicator of thermal sensitivity, is examined by dispensing agiven quantity of foam and photographing sequentially its appearancewith time during incubation at 36° C. Simple collapse time can bemeasured by applying a foam sample on a body surface like the fingers atnormal body temperature of about 37° C.

Oils may cause foam to be thermolabile and “quick breaking.” However, incertain embodiments herein, despite the presence of high oil content,quite unexpectedly the foam is substantially thermally stable. By“substantially thermally stable” it is meant that the foam uponapplication onto a warm skin or body surface at about 35-37° C. does notcollapse within about 30 seconds. Thus, in one or more embodiments thesimple collapse time of the foam is more than about 30 seconds or morethan about one minute or more than about two minutes. In one or morelimited embodiments simple collapse time can be a little shorter than 30seconds, but not less than about 20 seconds. In one or further oralternative embodiments the collapse time is measured by introducing asample of foam into an incubator at 36° C. and the collapse time of thefoam is more than 30 seconds or more than about one minute or more thanabout two minutes.

Water Activity

The term “water activity” as used herein, activity represents thehydroscopic nature of a substance; or the tendency of a substance thatabsorbs water from its surroundings. Microorganisms require water togrow and reproduce, and such water requirements are best defined interms of water activity of the substrate. The water activity of asolution is expressed as Aw=P/Po, where P is the water vapor pressure ofthe solution and Po is the vapor pressure of pure water at the sametemperature. Every microorganism has a limiting Aw, below which it willnot grow; e.g., for Streptococci, Klebsiella spp, Escherichia coli,Clostridium perfringens, and Pseudomonas spp, the Aw value is 0.95.Staphylococcus aureus is most resistant and can proliferate with an Awas low as 0.86, and fungi can survive at Aw of at least 0.7. In one ormore embodiments, the concentration of the hydrophobic oil in the gel orfoam composition is sufficient to provide an Aw value selected from theranges of (1) about 0.8 and about 0.9; (2) about 0.7 and about 0.8; and(3) less than about 0.7. By delivering the formulation in a pressurizedpackage does not allow for humidity to be absorbed by the preparation,and therefore, the water free character of the composition cannot bedamaged.

Tetracycline

The primary active agent in accordance with the present invention is atetracycline compound (herein “a tetracycline” or “tetracyclines”) or apharmaceutically acceptable salt or hydrate thereof substantiallystabilized in a base. The tetracyclines are characterized by a carbonskeleton composed of four linearly fused six-membered carbon rings(octahydrotetracene-2-carboxamide Skeleton). They are defined as “asubclass of polyketides having an octahydrotetracene-2-carboxamideskeleton”. They are collectively known as “derivatives of polycyclicnaphthacene carboxamide”.

Non-limiting examples of tetracyclines, include the naturally-occurringTetracycline, Chlortetracycline, Oxytetracycline and Demeclocycline, thesemi-synthetic Doxycycline, Lymecycline, Meclocycline, Methacycline,Minocycline, Rolitetracycline, Chlorotetracycline and Tigecycline.

The tetracyclines can be present in a free base form a hydrate form, asalt form or a complex form. For example, minocycline can be present asthe base form, as well as a hydrate or a hydrochloride salt.

Notably, various tetracyclines have different hydrophilic/hydrophobiccharacters. For example, the Log Kp (log of the of distribution constantat pH 7.0; buffer/CHCl₃) is 1.91, which means that it is highlyhydrophilic. The Log Kp of Doxycycline is 0.2; and the Log Kp ofMinocycline is −1.6, which stands for hydrophobic character of thiscompound (see Leive L et al, “Tetracyclines of various hydrophobicitiesas a probe for permeability of Escherichia coli outer membrane”,Antimicrobial Agents and Chemotherapy 1984:25, 539-544). Whilst anytetracycline compound is suitable as an active agent according to thepresent invention, there is preference to tetracycline compounds whichare more hydrophobic. Thus, in an embodiment of the present inventionthe active agent is selected as one that has Log Kp equal to, or lowerthan about 0.2.

In an embodiment, the tetracycline antibiotic is hydrophobic due to thefact that it does not comprise any hydroxy group at Carbons 5, 6, and 7.

In certain embodiments, the tetracycline is selected from the groupconsisting of doxycycline and minocycline; and in a certain embodimentthe tetracycline is minocycline.

According to the present invention, the tetracycline is employed in anamount ranging from about 0.001% to about 10%; or in an amount rangingfrom about 0.025% to about 6%; or in an amount ranging from about 0.1%to about 3%, by weight of the foamable composition.

The tetracycline in accordance to the present invention is insoluble oris partially soluble in the whole composition and all or part thereof issuspended. It is known that every chemical compound has differentsolubility in different solvents or compositions, and therefore it isnot possible to provide a general list compounds that are not soluble orpartially soluble or suspended in the composition. However, anytetracycline active agent, as exemplified herein, is suitable asinsoluble or partially soluble or suspended, if visual or microscopicobservation demonstrates crystals or particles of such active agent inthe oleaginous composition.

In additional embodiments, the concentration of the tetracycline isdetermined by its ability to inhibit the occurrence of apoptosis in anex-vivo human skin model; or by its ability to inhibit the occurrence ofpro-inflammatory cytokines in an ex-vivo human skin model. In alternateembodiments, the concentration of the tetracycline is higher than thelowest concentration which results in intradermal delivery of sufficientconcentrations of the tetracycline when tested in the Franz-cell invitro model, using human or pig's skin.

Hydrophobic Oil

The term “hydrophobic oil” relates to a material, having solubility indistilled water at ambient temperature of less than about 1 gm per 100mL, or less than about 0.5 gm per 100 mL, or less than about 0.1 gm per100 mL. The hydrophobic oil is a liquid at ambient (room) temperature,e.g., about 20-30° C.

In an embodiment, the topical therapeutic composition comprises at leastone hydrophobic oil, selected from the group consisting of a mineraloil, a hydrocarbon oil, an ester oil, a triglyceride oil, an oil ofplant origin, an oil from animal origin, an unsaturated orpolyunsaturated oil, a diglyceride, a PPG alkyl ether and a siliconeoil.

As exemplified herein, members of each of the above listed groups ofhydrophobic oils have been found to be compatible with hydrophobictetracyclines, such as minocycline and doxycycline.

Non-limiting examples of hydrocarbon oils include mineral oil, liquidparaffin, an isoparaffin, a polyalphaolefin, a polyolefin,polyisobutylene, a synthetic isoalkane, isohexadecane and isododecane.

Non-limiting examples of ester oils include alkyl benzoate, alkyloctanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate, arachidylbehenate, arachidyl propionate, benzyl laurate, benzyl myristate, benzylpalmitate, bis (octyldodecyl stearoyl) dimer dilinoleate, butylmyristate, butyl stearate, cetearyl ethylhexanoate, cetearylisononanoate, cetyl acetate, cetyl ethylhexanoate, cetyl lactate, cetylmyristate, cetyl octanoate, cetyl palmitate, cetyl ricinoleate, decyloleate, diethyleneglycol diethylhexanoate, diethyleneglycol dioctanoate,diethyleneglycol diisononanoate, diethyleneglycol diisononanoate,diethylhexanoate, diethylhexyl adipate, diethylhexyl malate,diethylhexyl succinate, diisopropyl adipate, diisopropyl dimerate,diisopropyl sebacate, diisosteary dimer dilinoleate, diisostearylfumerate, dioctyl malate, dioctyl sebacate, dodecyl oleate, ethylhexylpalmitate, ester derivatives of lanolic acid, ethylhexyl cocoate,ethylhexyl ethylhexanoate, ethylhexyl hydroxystarate, ethylhexylisononanoate, ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexylstearate, hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetylisocetyl behenate, isocetyl lanolate, isocetyl palmitate, isocetylstearate, isocetyl salicylate, isocetyl stearate, isocetyl stearoylstearate, isocetearyl octanoate, isodecyl ethylhexanoate, isodecylisononanoate, isodecyl oleate, isononyl isononanoate, isodecyl oleate,isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyllanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate,isopropyl stearate, isostearyl behenate, isosteary citrate, isostearylerucate, isostearyl glycolate, isostearyl isononanoate, isostearylisostearate, isostearyl lactate, isostearyl linoleate, isostearyllinolenate, isostearyl malate, isostearyl neopentanoate, isostearylpalmitate, isosteary salicylate, isosteary tartarate, isotridecylisononanoate, isotridecyl isononanoate, lauryl lactate, myristyllactate, myristyl myristate, myristyl neopentanoate, myristylpropionate, octyldodecyl myristate, neopentylglycol dicaprate, octyldodecanol, octyl stearate, octyl palmitate, octyldodecyl behenate,octyldodecyl hydroxystearate, octyldodecyl myristate, octyldodecylstearoyl stearate, oleyl erucate, oleyl lactate, oleyl oleate, propylmyristate, propylene glycol myristyl ether acetate, propylene glycoldicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate,maleated soybean oil, stearyl caprate, stearyl heptanoate, stearylpropionate, tocopheryl acetate, tocopheryl linoleate, glyceryl oleate,tridecyl ethylhexanoate, tridecyl isononanoate and triisocetyl citrate.

Non-limiting examples of triglycerides and oils of plant origin includealexandria laurel tree oil, avocado oil, apricot stone oil, barley oil,borage seed oil, calendula oil, canelle nut tree oil, canola oil,caprylic/capric triglyceride castor oil, coconut oil, corn oil, cottonoil, cottonseed oil, evening primrose oil, flaxseed oil, groundnut oil,hazelnut oil, glycereth triacetate, glycerol triheptanoate, glyceryltrioctanoate, glyceryl triundecanoate, hempseed oil, jojoba oil, lucerneoil, maize germ oil, marrow oil, millet oil, neopentylglycoldicaprylate/dicaprate, olive oil, palm oil, passionflower oil,pentaerythrityl tetrastearate, poppy oil, propylene glycol ricinoleate,rapeseed oil, rye oil, safflower oil, sesame oil, shea butter, soya oil,soybean oil, sweet almond oil, sunflower oil, sysymbrium oil, syzigiumaromaticum oil, tea tree oil, walnut oil, wheat germ glycerides andwheat germ oil.

Non-limiting examples of PPG alkyl ethers include PPG-2 butyl ether,PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butylether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-15 stearyl ether,PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-20 butylether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether,PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butylether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether,PPG-30 cetyl ether, PPG-50 cetyl ether, PPG-30 isocetyl ether, PPG-4lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methylether, PPG-3 myristyl ether, PPG-4 myristyl ether, PPG-10 oleyl ether,PPG-20 oleyl ether, PPG-23 oleyl ether, PPG-30 oleyl ether, PPG-37 oleylether, PPG-40 butyl ether, PPG-50 oleyl ether and PPG-11 stearyl ether.Preferred PPG alky ethers according to the present invention includePPG-15 stearyl ether, PPG-2 butyl ether and PPG-9-13 butyl ether.

Non-limiting examples of oils from animal origin include herring oil,cod-liver oil and salmon oil.

Non-limiting examples of silicone oils include cyclomethicone, adimethyl polysiloxane, dimethicone, an epoxy-modified silicone oil, afatty acid-modified silicone oil, a fluoro group-modified silicone oil,a methylphenylpolysiloxane, phenyl trimethicone and a polyethergroup-modified silicone oil.

Viscosity-Modifying Agent

A viscosity-modifying agent, in the context of the present invention isan agent which, when added to a hydrophobic oil, facilitates thecreation of a hydrophobic breakable vehicle in the form of a breakableoil gel breakable oil foam. The term “breakable” refers to a uniqueproperty of the oil gel or the foam wherein said oil gel foam is stableupon dispensing from a container, yet breaks and spreads easily uponapplication of mild shear force.

The at least one viscosity-modifying agent is selected from the groupconsisting of a fatty alcohol, a fatty acid and a wax, wherein saidfatty alcohols and/or fatty acids have at least 12 carbon atoms in theircarbon backbone.

Fatty Alcohols and Fatty Acids

Preferably, the fatty alcohol and/or fatty acid and/or wax are solid atambient temperature. In certain embodiments, the fatty alcohol and/orthe fatty acid and/or the wax or the mixture of them have a meltingpoint of more than about 40° C.

In an embodiment of the present invention, the fatty alcohol is selectedfrom the group consisting of lauryl alcohol, myristyl alcohol, cetylalcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol,tetracosanol, hexacosanol, octacosanol, triacontanol, tetratriacontanol.In an embodiment of the present invention, the fatty acid is selectedfrom the group consisting of dodecanoic acid, tetradecanoic acid,hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoicacid, docosanoic acid, tetracosanoic acid, hexacosanoic acid,heptacosanoic acid, octacosanoic acid, triacontanoic acid,dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid andpentatriacontanoic acid.

In certain embodiments, the carbon chain of said fatty alcohol or saidfatty acid is substituted with a hydroxyl group; and in an additionalembodiment said fatty acid is 12-hydroxy stearic acid.

Waxes

Waxes that can be used as part of the viscosity-modifying agent includeplant waxes, such as carnauba wax, candelilla wax, ouricury wax,sugarcane wax, retamo wax and jojoba oil; animal waxes, such as beeswax;petroleum derived waxes, including paraffin waxes which are mixtures ofsaturated of n- and isoalkanes, naphthenes, and alkyl- andnaphthene-substituted aromatic compounds; and polyethylene and relatedderivatives.

In an embodiment the wax is selected from the group consisting ofvegetable wax, beeswax, chinese wax, cotton wax, bayberry wax,candelilla wax, carnauba wax, castor wax, cuban palm wax, esparto wax,fir wax, flax wax, flower wax, fat wax, japan wax, sandy wax, lanolinwax, ouricury wax, palm waxes, rice bran wax, rice-oil wax, shellac wax,soy wax, sugar cane wax, ucuhuba wax, a hydrogenated oil, hydrogenatedcastor oil, hydrogenated cottonseed oil, or hydrogenated jojoba oil,mink wax, montan wax, ozokerite, PEG-6 beeswax, rezo wax, spent grainwax, stearyl dimethicone, a paraffin wax, paraffin 58-62° C. wax,paraffin 51-53° C. wax, paraffin 42-44° C. wax, synthetic mineral wax,fischer-tropsch wax, duroxon wax, or polymekon wax, synthetic waxes,albacer wax, atlasene wax, BASF waxes, cardis waxes, ceramid, glycowaxes, flexo wax, or oxazoline waxes, as well as other waxes, asdescribed in “The Complete Technology Book on Wax and Polishes,Publisher: Asia Pacific Business Press Inc., 2006”

Mixtures of Fatty Alcohols, Fatty Acids and Waxes

It is to be understood that at least one viscosity-modifying agent isrequired, but that combinations of more than one viscosity-modifyingagent are contemplated. In certain embodiments, a combination of twoviscosity-modifying agents is preferred. In certain embodiments, theviscosity-modifying agent combination contains at least one fattyalcohol and at least one fatty acid; or at least one fatty alcohol andleast one wax; or at least one fatty acid and at least one wax; or atleast one fatty alcohol, at least one fatty acid and least one wax.

In one or more embodiments the range of ratio of fatty alcohol to fattyacid; or fatty alcohol to wax is about 100:1 to about 1:100; or about90:1 to about 1:45; or about 80:1 to about 1:40; or about 70:1 to about1:35; or about 60:1 to about 1:30; or about 50:1 to about 1:25; or about40:1 to about 1:20; or about 30:1 to about 1:15; or about 20:1 to about1:10; or about 15:1 to about 1:5; or about 10:1 to about 1:1; or anyranges in between such as 1:20 to 20:1, or preferably from 1:10 to 10:1,or 1:4 to 4:1, or 2:3 or 3:2.

In certain embodiments, the total concentration of viscosity-modifyingagents can be about 0.1% to about 40% by weight; or about 0.4% to about18% by weight; or about 1% to about 12% by weight.

In certain other embodiments, the composition comprisesviscosity-modifying agents from two classes (e.g., at least one fattyalcohol and at least one fatty acid; or at least one fatty alcohol andat least one wax; or at least one fatty acid and at least one wax); andthe concentration of each class respectively is within any one of thefollowing ranges (i) between about 0.1% and about 1%, (ii) between about1% and about 5%, (iii) between about 5% and about 10%, or (iv) betweenabout 10% and about 20%.

Additional Active Agents

Since conditions that can be treated with a tetracycline are oftenassociated with additional conditions, such as inflammation andinfection by other microorganisms (other than bacteria), a combinationof the tetracycline, and an additional active agent, suitable for thetreatment of the underlying disorder or another disorder whichsubstantially concurrently occurs in the same patient is useful forsimultaneous therapy of the patient's condition.

Suitable active agents include but are not limited to an active herbalextract, an acaricides, an age spot and keratose removing agent, anallergen, an alpha hydroxyl acid, an analgesic agent, an androgen, anantiacne agent, an antiallergic agent, an antiaging agent, anantibacterial agent, an antibiotic, an antiburn agent, an anticanceragent, an antidandruff agent, an antidepressant, an antidermatitisagent, an antiedemic anent, an antifungal agent, an antihistamine, anantihelminth agent, an anti-hyperkeratosis agent, an anti-infectiveagent, an antiinflammatory agent, an antiirritant, an antilipemic agent,an antimicrobial agent, an antimycotic agent, an antioxidant, anantiparasitic agent, an antiproliferative agent, an antipruritic agent,an antipsoriatic agent, an antirosacea agent, an antiseborrheic agent,an antiseptic agent, an antiswelling agent, an antiviral agent, ananti-wart agent, an anti-wrinkle agent, an antiyeast agents, anastringent, a beta-hydroxy acid, benzoyl peroxide, a topicalcardiovascular agent, a chemotherapeutic agent, a corticosteroid, animmunogenic substance, a dicarboxylic acid, a disinfectant, an estrogen,a fungicide, a hair growth regulator, a haptene, a hormone, a hydroxyacid, an immunosuppressant, an immunoregulating agent, animmunomodulator, an immunostimulant, an insecticide, an insectrepellent, a keratolytic agent, a lactam, a local anesthetic agent, alubricating agent, a masking agent, a metals, a metal oxide, a mitocide,a neuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a pesticide, a protein, a photodynamictherapy agent, a progesterone, a radical scavenger, a refatting agent, aretinoid, a sanative, a scabicide, a sedative, a self tanning agent, askin protective agent, a skin whitening agent, a steroid, a steroidhormone, a vasoactive agent, a vasoconstrictor, a vasodilator, avitamin, a vitamin A, a vitamin A derivative, a vitamin B, a vitamin Bderivative, a vitamin C, a vitamin C derivative, a vitamin D, a vitaminD derivative, a vitamin D analog, a vitamin F, a vitamin F derivative, avitamin K, a vitamin K derivative, a wound healing agent and a wartremover.

Incompatible Excipients and Undesirable Excipients

In certain embodiments, the composition is free of petrolatum, surfaceactive agents, protic solvents, certain polar aprotic solvents andsilicone thickening agents; and in certain embodiments the foamablecomposition is substantially free of such excipients. In the contextherein, the term “substantially-free” relates to a composition thatcontains a total of less than about 0.4% of petrolatum, surface activeagents, protic solvents, certain polar aprotic solvents and siliconethickening agents cumulatively. Preferably, the composition comprisesless than about 0.2% by weight of petrolatum, surface active agents,protic solvents, certain polar aprotic solvents and silicone thickeningagents cumulatively and more preferably less than about 0.1%.

Surface Active Agents

Surfactants have been categorized in to various sub classes depending onthere ionic characteristics, namely non-ionic surfactants, anionic,cationic, zwitterionic, amphoteric and amphiphilic surfactants.Surfactants of all kinds are undesirable in accordance with the presentinvention, as (i) they were found to cause degradation of thetetracycline antibiotic; and (ii) they are generally known to possessirritation potential.

Non-limiting examples of classes of non-ionic surfactants that areundesirable according to the present invention include: (i)polyoxyethylene sorbitan esters (polysorbates), such as polysorbate 20,polysorbate 40, polysorbate 60 and polysorbate 80; (ii) sorbitan esters,such as Sorbitan monolaurate and sorbitan monooleate; (iii)polyoxyethylene fatty acid esters, such as, PEG-8 Stearate, PEG-20Stearate, PEG-40 Stearate, PEG-100 Stearate, PEG-150 Distearate, PEG-8laurate, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-8 oleate,PEG-9 oleate, PEG-10 oleate, PEG-12 oleate, PEG-15 oleate and PEG-20oleate; (iv) PEG-fatty acid diesters; (v) polyethylene glycol (PEG)ethers of fatty alcohols; (vi) glycerol esters, such as glycerylmonostearate, glyceryl monolaurate, glyceryl monopalmitate and glycerylmonooleate; (vii) PEG-fatty acid mono- and di-ester mixtures; (viii)polyethylene glycol glycerol fatty acid esters; (ix) propylene glycolfatty acid esters; (x) mono- and diglycerides; (xi) sugar esters (mono-,di- and tri-esters of sucrose with fatty acids) and (xii) polyethyleneglycol alkyl phenols.

In additional embodiments, the term “substantially surfactant-free”relates to a composition wherein the ratio between theviscosity-modifying agent and the surfactant is between 10:1 or 5:1; orbetween 20:1 and 10:1 or between 100:1 and 20:1.

In the context of the present invention, while fatty alcohols, fattyacids and certain waxes are amphiphatic, these substances are noteffective as stand-alone surfactants in foamable emulsion compositions,because of their very weak emulsifying capacity and further due to theirweak foaming capacity on their own. Hence, fatty alcohols, fatty acidsand certain waxes, which constitute the viscosity-modifying agent of thepresent invention, are not undesirable.

Protic Solvents

Protic solvents, such as short chain alcohols, glycols and glycerin areincompatible with tetracyclines and therefore they are undesirable.

Aprotic Polar Solvents

We discovered that certain polar aprotic solvents are incompatible withtetracycline antibiotics. Thus, aprotic polar solvents, such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, acetone, methylethyl ketone, 1,4-Dioxane and tetrahydrofuran (THF),N-methylpyrrolidone, pyridine, piperidine, dimethylformanide,N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone) and azone(1-dodecylazacycloheptan-2-one) are undesirable.

Silicone Thickening Agents

Silicone thickening agents comprise one or more polysiloxane-derivedcomponents. Such polysiloxanes are typically cross-linked and they haverubber-like characteristics, which require their solubilization in anoil, usually a silicone oil. An example of such a silicone thickeningagent is ST-Elastomer 10 (Dow Corning), is a mixture of high molecularweight dimethicone crosspolymer (12%), in cyclopentasiloxane(cyclomethicone, silicone solvent). With reference to bioavailability ofan active agent in the skin following topical application, it isconceivable that cross co-polymers will create a non permeable filmwhich should block skin penetration and therefore, it is undesirable.Further, in the context of a breakable foam, cyclomethicone is know as adefoamer and therefore it presence in high concentrations in thebreakable hydrophobic composition is undesirable.

In one or more other specific embodiments the drug carrier is formulatedsubstantially free of elastomers. In one or more other specificembodiments the drug carrier is formulated essentially free ofelastomers. In one or more other specific embodiments the drug carrieris formulated substantially free of silicones. In one or more otherspecific embodiments the drug carrier is formulated essentially free ofsilicones. In one or more other specific embodiments the drug carrier isformulated with less than about 30% silicone, or less than about 25%silicone, or less than about 20% silicone, or less than about 15%silicone, or less than about 10% silicone, or less than about 7.5%silicone, or less than about 5% silicone or less than about 2% silicone;or less than about 1% silicone; or less than about 0.5% silicone.

Petrolatum

Petrolatum, also termed “Vaseline”, can be disadvantageous, due to itsgreasy nature. It is known to leave greasy and sticky feeling afterapplication and occasionally stain cloths. Thus, white petrolatum andother semi-solid oils are not a preferred hydrophobic oil according tothe present invention. Additionally, compositions containing asubstantial amount of semi-solid hydrophobic oils, e.g., whitepetrolatum, as the main ingredients of the oil phase of the emulsion,will likely exhibit high viscosity and poor flowability and can beinappropriate candidates for a foamable composition. Thus in one or moreembodiments semi-solid hydrophobic oils are a subsidiary component inthe composition, for example being present at less than about 25%, lessthan about 20%, less than about 15%, less than about 10%, or less thanabout 5% by weight of the hydrophobic breakable composition. In otherembodiments formulations with more than 50% petrolatum have been madewhich produce foam of excellent quality, a collapse time of in excess ofthree minutes.

Skin Penetration

Surprisingly, despite the fact that said tetracyclines are hydrophobicat neutral pH (especially minocycline), they do not dissolve in thehydrophobic oils, even at a concentration of 0.05%. So, it arises thatat any concentration of more than 0.1% the majority of the tetracyclineis suspended, rather than dissolved. However, whilst intuitively thebioavailability of the drug in the skin following topical application isexpected to be low, substantial amounts of the tetracycline are found inthe skin following one application, as shown in in-vitro skinpenetration tests. The amounts found in the skin following oneapplication of a hydrophobic breakable composition comprising 1%minocycline and 4% minocycline for 24 hours was 9.49 and 43.12 μg/cm²respectively. The weight of skin at the delivery area is about 100 mg,which implies that the concentration of minocycline in the skinfollowing 24 hours of exposure is about 90 μg/gr of skin for the 1%formulation and about 430 μg/gr for the 4% formulation. According to theliterature, the minimum inhibitory concentration (MIC) for minocyclineis less than 4 μg/mL, and therefore, it can be concluded that theconcentrations found in the skin are sufficient, or even higher thanrequired to treat bacterial skin infections.

Even more surprisingly, whilst the tetracycline penetrates well into theskin, the tetracycline does not permeate through the skin. This is avery important feature of the composition of the present invention, asit minimizes the probability of systemic side effects, when topicalapplication is carried out. In one or more embodiments there is no ornegligible transdermal delivery. In one or more embodiments the ratio ofintradermal to transdermal delivery is about or more than 100:1.

This means that the current hydrophobic vehicle of minocycline is uniquein targeting the delivery of the drug intra-dermally, rather thantransdermally.

In an embodiment, the concentration of the tetracycline in thehydrophobic breakable composition, when tested in the Franz-cell invitro model, using human or pig's skin is higher than the lowestintradermal concentration of the tetracycline that is required to killskin bacteria, such as staphylococcus and streptococcus strains.

Thus, in an embodiment, the composition, wherein, when tested in theFranz-cell in vitro model using human or pig's skin, affords an amountof the tetracycline in the skin which is higher than the respectiveamount transferred transdermally. In certain embodiments, when tested inthe Franz-cell in vitro model using human or pig's skin, the ratiobetween the amount of the tetracycline in the skin and the respectiveamount transferred transdermally is higher than about 100; or between100 and 10; or between 10 and 2; or more than 1.

Anti-Microbial Effect

In an in-vitro study, it was revealed that the hydrophobic breakablecomposition comprising 1% minocycline and 4% minocycline inhibited thegrowth of Streptococcus pyogenes, Pseudomonas aeruginosa, Staphylococcusaureus, as well as a methicillin-resistant strain of Staphylococcusaureus (MRSA). The formulation was also effective againstPropionbacterium acnes, the causative microorganism in acne.

This result was unexpected, as the minocycline was primarily suspendedin the composition, thus minimizing its expected availability for theantibacterial effect.

Anti-Inflammatory and Anti-Apoptosis Effect of the CompositionComprising a Tetracycline

This effect of minocycline, when treated after the induction ofinflammation is surprising, as the literature teaches that“pre-treatment, but not post-treatment, with minocycline markedlyattenuated increased pro-inflammatory cytokines release and oxidativeand nitrosative stress in mononeuropathic rats.” (see for example, PadiS S, Kulkarni S K, “Minocycline prevents the development of neuropathicpain, but not acute pain: possible anti-inflammatory and antioxidantmechanisms”, Eur J Pharmacol. 2008; 601:79-87). By contrast, whenminocycline was included in the hydrophobic breakable composition of thepresent invention and applied to skin specimens after induction of UVdamage, it significantly decreased apoptosis, as measured by caspase 3activity; and to elevate skin cell viability.

In an embodiment, the concentration of the tetracycline is determined byits ability to inhibit the occurrence of apoptosis; or by its ability todecrease caspase 3 activity or by its ability to decrease the occurrenceof pro-inflammatory cytokines in an ex-vivo human skin model.

Fields of Applications

The hydrophobic breakable tetracycline gel and foam compositions of thepresent disclosure are suitable for treating any inflicted surface. Inone or more embodiments, foamable carrier is suitable for administrationto the skin, a body surface, a body cavity or mucosal surface, e.g., thecavity and/or the mucosa of the nose, mouth, eye, respiratory system,vagina, urethra or rectum and the ear canal (severally andinterchangeably termed herein “target site”).

Many conditions can be contemplated based on the antimicrobialproperties of the tetracyclines, plus the anti-inflammatory,anti-oxidative and neuroprotective effects of certain tetracyclinecompound (such as minocycline and doxycycline).

By selecting a suitable tetracycline compound, or a combination of atetracycline with at least one additional active agent, the compositionof the present disclosure is useful in treating an animal or a humanpatient having any one of a variety of dermatological disorders,including, but not limited to the list, provided here in an alphabeticalmanner: abscess, acne, acne conglobata, acne fulminans, acne vulgaris,acne scars, acute febrile neutrophilic dermatosis, acute lymphangitis,allergic contact dermatitis, alopecia, athlete's foot, atopicdermatitis, bacterial skin infections, baldness, basal cell carcinoma,blisters, bromhidrosis, bullous pemphigoid, burn, calluses candidiasis,carbuncles, cellulitis, chemical burns, chicken pox, cholesteatoma,cholinergic urticaria, chronic effects of sunlight, cold sores, coldurticaria, comedones, corns, creeping eruption, cutaneous abscess,cutaneous larva migrans, cutaneous myiasis, dark spots, delusionalparasitosis, Dercum disease, dermatitis, dermatitis herpetiformis,dermatological pain, dermatological inflammation, dermographism,dermatophytoses, drug eruptions and reactions, dyshidrotic eczema,ectodermal dysplasia, eczema, ecthyma, epidermoid cyst, epidermalnecrolysis, erysipelas, erysipelas, erythrasma, exfoliative dermatitis,erythema multiforme, erythema nodosum, folliculitis, fungal nailinfections, fungal skin infections, furuncles, gangrene, genital herpes,granuloma annulare, head lice, hidradenitis suppurativa, hives,folliculitis, hirsutism, hyperhidrosis, hypohidrosis, ichthyosis,impetigo, inflammatory acne, ingrown nails, intertrigo, irritant contactdermatitis, ischemic necrosis, itching, jock itch, Kaposi's sarcoma,keratosis pilaris, lichen simplex chronicus, lichen planus, lichensclerosus, lymphadenitis, lymphadenitis, lymphangitis, malignantmelanoma, mastocytosis, measles, melanoma, melanoma, miliaria, moles,molluscum contagiosum, MRSA, necrotizing subcutaneous infection,necrotizing fasciitis, necrotizing myositis, nodular papulopustularacne, non-inflammatory acnce, nummular dermatitis, oral herpes,panniculitis, parapsoriasis paronychia, parasitic skin infections,pemphigus, photo-allergy, photo-damage, photo-irritation,photosensitivity, papules, pediculosis, perioral dermatitis, pimples,pityriasis rosea, pityriasis Lichenoides, pityriasis rosea, pityriasisrubra pilaris, poison ivy, post-operative or post-surgical skinconditions, pressure ulcers, pressure urticaria, pruritis,pseudofolliculitis barbae, psoriasis, PUPPP, purpura, pustules, pyogenicgranuloma, rash, ringworm, rosacea, roseola, rubella, scabies, scaldedskin syndrome, scarring, scleroderma, sebaceous cyst, seborrheicdermatitis, seborrheic keratosis, shingles, skin aging, skin cancer,skin neoplasia, skin neoplasms, skin rash, skin ulcers, squamous cellcarcinoma, staphylococcal scalded skin syndrome, stasis dermatitis,Stevens-Johnson syndrome, sunburn, sun spots, thermal burns, tineacorporis, tinea cruris, tinea pedis, tinea versicolor, toxic epidermalnecrolysis, trauma or injury to the skin, varicella zoster virus,vitamin D deficiency, viral skin infections, vitiligo, warts, waterhives, wrinkles, xerosis, yeast skin infections and zoster.

Likewise, the gel or foam composition of the present disclosure aresuitable for treating a disorder of a body cavity or mucosal surface,e.g., the surface and/or mucosa of the nose, mouth, eye, ear,respiratory system, vagina, urethra, or rectum. Non limiting examples ofsuch conditions include chlamydia infection, gonorrhea infection,hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genitalwarts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale,lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscumcontagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvardisorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy,vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvicinflammation, endometritis, salpingitis, oophoritis, genital cancer,cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginaldryness, dyspareunia, anal and rectal disease, anal abscess/fistula,anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids,anal itch, pruritus ani, fecal incontinence, constipation, polyps of thecolon and rectum.

In one or more embodiments, the hydrophobic breakable gel isspecifically useful for ophthalmic administration. Unlike customaryophthalmic ointments, which create a greasy film on the eye and blur thevision, the gel liquefies upon first eye blink and will spread on theeye surface.

Eye conditions that can be contemplated based on the antimicrobialproperties of the tetracycline, plus the anti-inflammatory,anti-oxidative and neuroprotective effects of certain tetracyclinecompound (such as minocycline and doxycycline) can be categorized, in anon limiting fashion by their symptoms as follows: eye redness, eye painor light sensitivity, blurred vision, loss of vision, visualdisturbances—floaters, flashing, distortion, halos, etc.,itching/burning, tearing/discharge, sensation of something in the eye,eyelid problems, double vision.

Examples of relevant conditions include macular degeneration,age-related macular degeneration, “dry” macular degeneration and “wet”macular degeneration, which are associated with photodamage andapoptosis, cataract, which is associated with apoptosis, glaucoma,open-angle glaucoma, closed-angle glaucoma (associated with opticalnerve death and apoptosis), retinopathy, proliferative diabeticretinopathy (apoptosis), macular Edema (inflammation), conjunctivitis,uveitis and trachoma (infection).

Non-limiting examples of ophthalmic conditions that can be treated by ahydrophobic breakable tetracycline composition of the present invention;or such conditions whose complications can be treated by saidcomposition; are provided herewith in their alphabetical order: allergy,blepharitis, cataract, central serous chorioretinopathy, color visionproblems, corneal abrasion, corneal edema, corneal ulcer,conjunctivitis, contact lens complications, dacryocystitis, blurreddistance vision, dry eye, eale's disease, episcleritis, eyelidectropion, eyelid entropion, eyelid cellulitis, eye strain, focusingspasm, glaucoma, acute glaucoma, iritis, keratoconus, lyme disease,macular degeneration, macular edema, macular hole, eye medicationtoxicity, myasthenia gravis, ocular cicatricial pemphigoid, ophthalmicmigraine, presbyopia, obstructed tear duct, optic neuritis, optic nervestroke, orbital fracture, orbital cellulitis, phlyctenulosis, pterygium,recurrent corneal erosion, retinal artery occlusion, retinal detachment,retinal tear, retinal vein occlusion, sarcoidosis, scleritis, sinusdisease, strabismus (ocular misalignment), subconjunctival hemorrhage,temporal arteritis, thyroid eye disease, trichiasis, eyelid tumor,twitching of eyelid (eyelid myokymia), uveitis, vitreous detachment andvitreous hemorrhage.

In light of the hygroscopic nature of the composition, it is furthersuitable for the treatment and prevention of post-surgical adhesions.Adhesions are scars that form abnormal connections between tissuesurfaces. Post-surgical adhesion formation is a natural consequence ofsurgery, resulting when tissue repairs itself following incision,cauterization, suturing, or other means of trauma. When comprisingappropriate protective agents, the foam is suitable for the treatment orprevention of post surgical adhesions. The use of foam is particularlyadvantageous because foam can expand in the body cavity and penetrateinto hidden areas that cannot be reached by any other alternative meansof administration.

In one or more embodiments, there is provided a composition for use inpreventing or ameliorating or treating photodamage or radiation damageor photoaging or reducing oxidative stress or inflammation in skinpathologies which are known to be accompanied by apoptic cell death orany two or more thereof.

In one or more embodiments, there is provided a composition for use inpreventing or ameliorating or treating a disorder, the tetracylinecomposition having at least one property or activity selected from alist including regenerative, anti-apoptotic, anti-inflammatory,anti-photodamaging anti-radiation damage and anti-photoaging.

In one or more embodiments, there is provided a composition comprising atetracycline for use in preventing protecting from or ameliorating ortreating UVB-induced skin damage.

In one or more embodiments, there is provided a composition comprising atetracycline for use in preventing, protecting from or ameliorating ortreating a disorder with symptoms including increased apoptosis and ordecreased cell viability, where the formulation acts to decreaseapoptosis and or increase cell viability. In one or more embodimentsthere is provided a composition for use in decreasing apoptosis and orincreasing cell viability.

In one or more embodiments, there is provided a composition comprising atetracycline for use in preventing or ameliorating or treating disordersby reducing oxidative stress and inflammation in skin pathologies whichare known to be accompanied by apoptotic cell death including rosaceaand impetigo.

In one or more embodiments there is provided a tetracycline compositionhaving regenerative, or anti-apoptotic, or anti-inflammatory, oranti-photodamaging, or anti-photoaging activity, or protective and ortherapeutic properties in the case of UVB-induced skin damage, or whichdecreases apoptosis and or increases cell viability, or in reducingoxidative stress and inflammation in skin pathologies accompanied byapoptotic cell death including rosacea and impetigo, or antibacterialactivity, or any two or more thereof.

Cosmetic Use

In one or more embodiments, the composition may be used for cosmeticuse. For example it may be used as part of a cosmetic formulation toprevent a cosmetic disorder or to improve the skin.

Administration

The compositions disclosed herein can be applied to the target site as agel or a foam. Application can be hourly, 2 hourly, 3 hourly, fourhourly, six hourly or eight hourly, twelve hourly, daily, alternate-dayor intermittent, as necessary. For reasons of compliance less frequentapplications, where possible are preferable such as twice-daily or dailysingle applications. In cases where prolonged or long term treatment isrequired a higher initial dose is provided followed by a gradualreduction to a lower maintenance dose, which can be increased if furtheroutbreaks occur.

EXAMPLES

The invention is described with reference to the following examples, ina non-limiting manner. The following examples exemplify the foamablecompositions and methods described herein. The examples are for thepurposes of illustration only and are not intended to be limiting. Manyvariations will suggest themselves and are within the full intendedscope.

Materials

Exemplary possible ingredients suitable for the production of foamablecompositions disclosed herein. Equivalent materials from othermanufacturers can also be used satisfactorily.

Chemical Name Function Commercial Name Supplier Beeswax white Foamadjuvant Beeswax white Henry Lamotte Behenyl alcohol Foam adjuvantLanette 22 Cognis Cetostearyrl alcohol Foam adjuvant Speziol C16-C18Cognis Cetyl alcohol Foam adjuvant Speziol C16 Cognis Coconut oilSolvent Coconut oil Henry Lamotte Cyclomethicone-5 SolventST-cyclomethicone-5 Dow Heavy Mineral Oil Solvent Paraffin oil liquidheavy Gadot Hydrogenated castor oil Foam adjuvant Cutina HR CognisIsostearic acid Foam adjuvant Isostearic acid Stearinerie Dubois LanolinFoam adjuvant Lanolin Spectrum Light Mineral Oil Solvent Pioner 2076PHansen & Rosenthal MCT Oil Solvent Captex 355 Abitec Minocycline HGlActive agent Minocycline HCl Hovione Myristyl alcohol Foam adjuvantSpeziol C14 Cognis Octyldodecanol Solvent Eutanol G Cognis Paraffin wax51-53 Wax Paraffin 51-53 Merck PPG 15 stearyl ether Solvent Arlamol EUniqema Propane/Isobutane/Butane Propellant A-46 Aeropres (20:78:2)Propane/Isobutane/Butane Propellant AP-70 Aeropres (55:18:27) Silicondioxide Dispersant Aerosil R 972 PH Evonik-Goldschmidt GmbH Soybean oilSolvent Soybean oil Spectrum Stearic acid Foam adjuvant Edenol ST1MCognis Stearyl Alcohol Foam adjuvant Speziol C18 Cognis

Part A—Gel Formulations Example 1—General Manufacturing Procedures for aGel

The following procedures are used to produce gel samples described inthe examples below, in which only the steps relevant to each formulationare performed depending on the type and nature of ingredients used.

Step 1: Hydrophobic oil are heated to 60-70° C.

Step 2: Fatty alcohols if present, fatty acids if present, wax ifpresent, are added to the hydrophobic oil and the formulation is mixeduntil complete melting.

Step 3: The formulation is cooled down to 30-40° C., the tetracyclineantibiotic is added and the formulation is mixed until homogeneity isobtained.

Step 4: The formulation is cooled down to room temperature under mixingand packaged into suitable containers.

By way of non-limiting example, tests are briefly set out below as wouldbe appreciated by a person of the art.

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 20, 10, 5 and 1 RPM. Viscosity is usuallymeasured at 10 RPM. However, at the apparent upper limit for the spindleof about 50,000 CP, the viscosity at 1 RPM may be measured, although thefigures are of a higher magnitude.

Chemical Stability: the amount of the tetracycline antibiotic isanalyzed chromatographically. Analysis is carried out after formulationpreparation and at appropriate time intervals thereafter. The samplesare typically stored in controlled temperature incubators at one or moreof 5° C., 25° C. and 40° C. for several weeks or months. At appropriatetime intervals samples are removed from the incubators and theconcentration of active agent is measured.

Example 2—Gel Formulations with Low Viscosity

The different hydrophobic oils suitable for use in topicalpharmaceutical compositions are generally liquid oils have a lowviscosity. When these oils are used as-is for active agents topicaldelivery, they have inter alia two non desirable properties: (1) becauseof their low viscosity, they tend to drop and to be runny and thereforenot easy for the patient to apply onto the skin, (2) they have poorsuspending properties leading to the rapid sedimentation ofnon-dissolved active ingredients (APIs), as described in Table 2.

TABLE 2 Low viscosity oleaginous preparations 001P 001 002P 002Formulations % w/w % w/w % w/w % w/w Ingredients Heavy mineral oil 75.0075.00 — — Light mineral oil 25.00 25.00 — — Soybean oil — — 100 100Total 100.00 100.00 100.00 100.00 Minocycline HCl — 0.1 — 0.1 ResultsViscosity at 10 rpm (cP) 96 92 47 49

As shown in formulations 001P and 002P, mixtures of mineral oils andsoybean oil have a low viscosity. Formulations 001 and 002, show thatafter the addition of Minocycline HCl, the viscosity of the formulationremains unchanged and that the active ingredient sediments.

Example 3—Mineral Oil-Based Formulations with Improved Viscosity

The influence of the combination of a tetracycline with fatty alcohols,fatty acids and waxes on formulation viscosity was assessed, asdescribed in Table 3a. Formulations containing a mixture of mineral oilswith fatty alcohols, fatty acids or waxes were prepared, and theirviscosity was measured before and after the addition of a tetracycline,namely minocycline HCl. Table 3a below presents the results offormulation viscosity before and after the addition of a tetracycline,as well as the percentage of viscosity increase due to the addition ofthe active ingredient.

TABLE 3a Combination of a tetracycline with fatty alcohols, fatty acidand waxes 003 004 005 005B Formulations % w/w % w/w % w/w % w/wIngredients Heavy mineral oil 65 65 65 65 Light mineral oil 25 25 25 30Stearyl alcohol 10 — — — Stearic acid — 10 — — Beeswax — — 10 —Hydrogenated Castor oil — — — 5 Total 100.00 100.00 100.00 100.00Results Viscosity Results at 10 rpm (cP) Without Minocycline HCl 9511858 942 848 With 0.1% Minocycline HCl 2652 8142 1695 6223 % ViscosityIncrease +179% +338% +80% +634%

Very surprisingly, it was discovered that the addition of minocyclineHCl to mineral oil-based formulations 003 to 005B led to a verysubstantial increase in viscosity, despite the very low amount ofminocycline HCL used, namely 0.1%. This totally unexpected results showthat the combination of a tetracycline, even at very low concentrations,with fatty alcohols, fatty acids or waxes has a strong synergisticeffect on oleaginous formulation viscosity.

The influence of the addition of different concentrations of atetracycline on a mineral oils-based formulation was then studied whenthe active ingredient is combined with a mixture of mineral oils, fattyalcohols, fatty acids and waxes, as described in Table 3b and 3c.

TABLE 3b Oleaginous preparations 238P Formulations % w/w IngredientsHeavy mineral oil 59.25 Light mineral oil 25.00 Cyclomethicone 5.00Stearyl alcohol 1.50 Beeswax 2.00 Stearic acid 2.00 Hydrogenated castoroil 1.50 Behenyl alcohol 1.00 Cetostealyl alcohol 2.50 Silicon dioxide0.25 Total 100.00 Minocycline HCl — Results Viscosity Results at 10 rpm(cP) 6639 % Viscosity Increase —

TABLE 3c Oleaginous preparations 238P 238A 238B 238C 238D Formulations %w/w % w/w % w/w % w/w % w/w Ingredients Formulation 238P 100.00 99.9099.80 99.50 99.00 Minocycline HCl — 0.10 0.20 0.50 1.00 ResultsViscosity Results at 6639 15789 18476 20876 20748 10 rpm (cP) %Viscosity Increase — +138% +178% +214% +213%

The combination of a tetracycline with a mixture of mineral oils, fattyalcohols, fatty acids and waxes has a strong synergistic effect andincreases the formulation viscosity. The viscosity of a formulationcontaining 0.50% minocycline HCl is about three times higher than theviscosity of the placebo formulation. The effect on the formulationviscosity is directly related to the concentration of the tetracycline:the higher the tetracycline concentration, the higher the viscosity ofthe formulation. In formulation 238, it appears that the viscosityincreasing effect of minocycline HCl reaches a plateau when the activeingredient is present at a concentration of about 0.50%.

In one or more embodiments, there is provided an oleaginous formulationcontaining mineral oils and a tetracycline in synergistic combinationwith a fatty alcohol, and/or a fatty acid and/or a wax, wherein theviscosity of the formulation is increased by the addition of the activeingredient by more than about 50%, more than about 100%, more than about200%, more than about 300%, more than about 500%.

In one or more embodiments, there is provided an oleaginous formulationcontaining hydrophobic oils, an active ingredient in synergisticcombination with a solidifying agent, wherein the viscosity of theformulation is increased by the addition of the active ingredient bymore than about 50%, more than about 100%, more than about 200%, morethan about 300%, more than about 500%.

In one or more embodiments, there increase in the formulation viscosityis related to the concentration of the active agent.

In one or more embodiments, the viscosity of the formulation is directlyproportional to the concentration of the active agent: the higher theconcentration of the active ingredient, the higher the formulationviscosity.

In one or more embodiments, the viscosity increasing effect of theactive ingredient reaches a plateau when the concentration of the activeingredient is increased.

In one or more embodiments, the viscosity of the formulation containingthe active ingredient is twice the viscosity of the sample formulationwhen the active ingredient is present at a concentration of less thanabout 10%, less than about 5%, less than about 1%, less than about 0.5%,less than about 0.1%, less than about 0.05%, less than about 0.01%.

Example 4—Vegetable Oils-Based Formulations with Improved Viscosity

Formulation with different vegetable oils, such as soybean oil andcoconut oil were prepared as described in Table 4a, to study theinfluence of the combination of a tetracycline with a fatty alcohol onformulation viscosity.

TABLE 4a Formulation based on vegetable oils 006 007 Formulations % w/w% w/w Ingredients Soybean oil 90 — Coconut oil — 90 Stearyl alcohol 1010 Total 100.00 100.00 Minocycline HCl — 1.15 Results Viscosity Resultsat 10 rpm (cP) Without Minocycline HCl 2771 24571 With 0.1% MinocyclineHCl 1826 22459 % Viscosity Increase −34% −9%

In contrast with the phenomenon observed with mineral oil-basedformulations, no increase in the viscosity was observed with thevegetable oils-based formulation when a tetracycline is combined with afatty alcohol.

The influence of the addition of a tetracycline on vegetable oils-basedformulations was then studied when the active ingredient is combinedwith a mixture of vegetable oils, fatty alcohols, fatty acids and waxes,as described in Table 4b.

TABLE 4b Formulation based on vegetable oils with improved viscosity244P 244B 244A Formulations % w/w % w/w % w/w Ingredients Soybean oil50.00 50.00 50.00 Coconut oil 23.60 23.60 23.60 Light Mineral oil 5.554.40 0.95 Cyclomethicone 5.00 5.00 5.00 Cetostearyl alcohol 3.50 3.503.50 Stearic acid 3.00 3.00 3.00 Myristyl alcohol 2.50 2.50 2.50Hydrogenated castor oil 2.00 2.00 2.00 Beeswax 2.00 2.00 2.00 Stearylalcohol 1.50 1.50 1.50 Behenyl alcohol 1.10 1.10 1.10 Silicon dioxide0.25 0.25 0.25 Total 100.00 100.00 100.00 Minocycline HCl — 1.15 4.60Results Viscosity Results at 10 rpm (cP) 7214 14429 17084 % ViscosityIncrease — +100% +137%

As shown in Table 4b, unexpectedly, the combination of a tetracyclinewith a mixture of hydrophobic oils, fatty alcohols, fatty acids andwaxes has a strong synergistic thickening effect and increases theformulation viscosity. The viscosity of a formulation containing 1.15%Minocycline HCl was about twice higher than the viscosity of the placeboformulation. Moreover, the effect on the formulation viscosity wasdirectly related to the concentration of the tetracycline: the higherthe tetracycline concentration, the higher the viscosity of theformulation.

Thus, in one or more embodiments, there is provided an oleaginousformulation containing vegetable oils and a tetracycline in synergisticcombination with a fatty alcohol, a fatty acid and a wax, wherein theviscosity of the formulation is increased by the addition of the activeingredient by more than about 50%, more than about 100%, more than about200%, more than about 300%, more than about 500%.

In another experiment, a sample of formulation 244B gel was storedduring 6 months at 40° C. and tested for minocycline content uniformity.It was found that minocycline was homogeneously dispersed in theformulation, and remained so even after prolonged incubation at 40° C.Additionally, the assay of minocycline in the formulation did not changeafter 6 months of storage at 40° C. Thus, in one or more embodiments,there is provided a hydrophobic gel formulation wherein the tetracyclineis homogeneously dispersed the gel and remains homogeneously dispersedand stable after 6 months of incubation at 40° C.

Part B—Foam Formulations Example 5—General Manufacturing Procedures fora Foam

The following procedures are used to produce the foam samples describedin the examples below, in which only the steps relevant to eachformulation are performed depending on the type and nature ofingredients used.

Step 1: Hydrophobic oils such as mineral oils are mixed at roomtemperature. Others solvents such as silicones, if present, are added atroom temperature under mixing until formulation homogeneity is obtained.

Step 2: The formulation is warmed to 70-80° C. and solid compounds suchas fatty alcohols, fatty acids and waxes are added and mixed untilcomplete dissolution.

Step 3: The formulation is cooled down to 30-40° C. and active agentsare added under mixing until formulation homogeneity is obtained.

Step 4: The formulation is packaged in aerosol canisters which arecrimped with a valve, pressurized with propellant and equipped with anactuator suitable for foam dispensing. Optionally a metered dosage unitcan utilized, to achieved delivery of desirable and/or repeatablemeasured doses of foam.Step 5: Pressurizing is carried out using a hydrocarbon gas or gasmixture. Canisters are filled and then warmed for 30 seconds in a warmbath at 50° C. and well shaken immediately thereafter.Tests

By way of non-limiting examples certain tests to characterize the foamand its stability are briefly set out below.

Collapse Time

Collapse Time, which is the measure of thermal stability, is examined bydispensing a given quantity of foam and photographing sequentially itsappearance with time during incubation at 36° C. The collapse timeresult is defined as the time when the foam height reaches 50% of itsinitial height or if the foam has not yet reached 50% of its initialheight after say 180 seconds then the collapse time is recorded asbeing >180. By way of illustration one foam may remain at 100% of itsinitial height for three minutes, a second foam may reach 90% of itsinitial height after three minutes, a third foam may reach 70% of itsinitial height after three minutes, and a fourth foam may reach 51% ofits initial height after three minutes, nevertheless in each of thesefour cases the collapse time is recorded as >180 seconds since forpractical purposes for easy application by a patient to a target themajority of the foam remains intact for more than 180 seconds. If thefoam for example reaches 50% of its original height after say 100seconds it would be recorded as having a collapse time of 100 seconds.It is useful for evaluating foam products, which maintain structuralstability at skin temperature for at least 1 minute. Foams which arestructurally stable on the skin for at least one minute are termed“short term stable” carriers or foams.

Density

The foam product is dispensed into preweighed tubes of a known volumeand weight. Replicate measurements of the mass of foam filling the tubeare made and the density is calculated.

Viscosity

Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 atambient temperature and 10, 5 and 1 RPM. Viscosity is usually measuredat 10 RPM. However, at about the apparent upper limit for the spindle of˜>50,000 cPs, the viscosity at 1 RPM may be measured, although thefigures are of a higher magnitude. Unless otherwise stated viscosity ofthe pre-foam formulation (PFF) is provided. It is not practical to tryand measure the viscosity of the foamable formulation with regularpropellants since they have to be stored in sealed pressurized canistersor bottles. In order to simulate the viscosity in the foamableformulations with propellant an equivalent weight of pentane (a lowvolatile hydrocarbon) is added to and mixed with the pre-foamformulation and left overnight. The viscosity is then measured as above.

Chemical Stability

The amount of active agent present is analyzed chromatographically infoam released from various pressurized canisters. Analysis is carriedout at baseline and at appropriate time intervals thereafter. Thecanisters are typically stored in controlled temperature incubators atone or more of 5° C., 25° C. and 40° C. At appropriate time intervalscanisters are removed and the amount of active agent in the foam sampleis measured.

Bubble Size

Foams are made of gas bubbles entrapped in liquid. The bubble size anddistribution reflects in the visual texture and smoothness of the foam.Foam bubbles size is determined by dispensing a foam sample on a glassslide, taking a picture of the foam surface with a digital cameraequipped with a macro lens. The diameter of about 30 bubbles is measuredrelatively to calibration standard template. Statistical parameters suchas mean bubble diameter, standard deviation and quartiles are thendetermined. Measuring diameter may also be undertaken with imageanalysis software. The camera used was a Nikon D40X Camera (resolution10 MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mm F2.8 EX DGHSM). Pictures obtained are cropped to keep a squared region of 400pixels×400 pixels.

Microscopic Observation

The light microscope enables observing and measuring particles from fewmillimeters down to one micron. Light microscope is limited by thevisible light wavelength and therefore is useful to measuring size ofparticles above 800 nanometers and practically from 1 micron (1,000nanometers).

Shakability

Shakability represents the degree to which the user is able to feel/hearthe presence of the liquid contents when the filled pressurized canisteris shaken. Shaking is with normal mild force without vigorous shaking orexcessive force. When the user cannot sense the motion of the contentsduring shaking the product may be considered to be non-shakable. Thisproperty may be of particular importance in cases where shaking isrequired for affecting proper dispersion of the contents.

Table of Shakability scoring Good shakability (conforms to requiredquality specification) 2 Moderate shakability (conforms to requiredquality 1 specification) Not shakable (fails to meet required qualityspecification) 0 but may still be flowable and allow foam formation ofquality Is substantially not able to pass through valve BlockCentrifugation

The centrifugation used in this procedure serves as a stress conditionsimulating the aging of the liquid formulation under investigation.Under these conditions, the centrifugal force applied facilitatescoalescence of dispersed globules or sedimentation of dispersed solids,resulting in loss of the desired properties of the formulation.

Centrifugation can also be executed at a higher rpm for a shorter periodor a lower rpm for a longer period bearing in mind the G-forceexperienced by the formulations is many fold greater than the one G towhich a formulation would be exposed to during its shelf life.Centrifugation can also be executed at a higher rpm for the same period,say 3000 or 10,000 rpm to simulate an extremely high stress level.

Example 6—Surfactant—Free Hydrophobic Foam Formulations

Surface active agents are known to be useful foaming agents, and thus itis not obvious to produce good quality foams free of surfactants. Asshown table 6 below, formulations 001F and 002F containing a mixture ofheavy mineral oil and light mineral oil with or without cyclomethiconefail to produce foams and release only liquids from the pressurizedcanisters. Compounds other than customary surfactants have beenidentified below that are suitable for the foaming of oleaginousvehicles.

TABLE 6 Oleaginous compositions 001F 002F Formulations % w/w % w/wIngredients Heavy mineral oil 75.00 70.00 Light mineral oil 25.00 25.00Cyclomethieone — 5.00 Total 100.00 100.00 Propellant A46 12.00 12.00Results Foam quality Poor Poor

Silicone oils such as cyclomethicone are included in the formulationsprimarily as cosmetic agent, for their contribution to skin feelingproperties. Volatile cyclomethicones can help reduce the greasy skinfeeling that may be present in oleaginous formulations.

Example 7—Surfactant Free Foams Containing Either Fatty Acid or FattyAlcohol

Two fatty acids were used in combination with heavy mineral oil, lightmineral oil and cyclomethicone, and tested for their foaming properties.As described in Table 7a below, formulation 003F containing isostearicacid (a liquid fatty acid) did not give rise to foam but merelygenerated bubbly liquids. Formulation 004F containing stearic acid (asolid fatty acid) initially produced a fairly good quality foam, butwhich was not stable and collapsed after 10 seconds. Likewise,compositions containing fatty alcohols produced fairly good qualityfoams that quickly collapsed (Table 7b). It follows that that fattyacids alone or fatty alcohols alone are not sufficient to stabilize ahydrophobic foam in the absence of a surfactant, even in reasonably highconcentrations.

TABLE 7a Compositions containing a fatty acid 003F 004F Formulations %w/w % w/w Ingredients Heavy mineral oil 60.00 60.00 Light mineral ail25.00 25.00 Cyelomethicone 5.00 5.00 Stearic acid (C18) — 10.00Isostearic acid (C18) 10.00 — Total 100.00 100.00 Propellant A46 12.0012.00 Results Foam quality Fair Fairly Good Collapse Time (sec) 10 10Foam density (/mL) — 0.071 PFF Viscosity (cP) 58 1442

TABLE 7b Compositions containing fatty alcohols 005 006 007 009Formulations % w/w % w/w % w/w % w/w Ingredients Heavy mineral oil 60.0060.00 60.00 60.00 Light mineral oil 25.00 25.00 25.00 25.00Cyclomethicone 5.00 5.00 5.00 5.00 Myristyl alcohol (C14) 10.00 — — —Cetyl alcohol (C16) — 10.00 — — Stearyl alcohol (C18) — — 10.00 —Behenyl alcohol (C22) — — — 10.00 Total 100.00 100.00 100.00 100.00Propellant A46 12.00 12.00 12.00 12.00 Results Foam quality Fair FairFair Fairly Good Collaps Time (sec) 10 10 10 10 Foam density (/mL) — — —0.160 PFF Viscosity (cP) 206 938 585 3839

Example 8—Surfactant Free Hydrophobic Foam Formulations Containing aCombination of Fatty Acids and Fatty Alcohols

Formulations were prepared, containing a combination of fatty acids andfatty alcohols and checked for their foaming properties. As described inTable 8 below, formulations 010 (containing stearic acid and myristylalcohol) and formulation 017 (containing isostearic acid and stearylalcohol) did not give rise to quality foams but merely generated bubblyliquids.

However, surprisingly, the combination of stearic acid with cetylalcohol, stearyl alcohol, cetostearyl alcohol or behenyl alcohol(without any surfactants) gave rise to good quality foams having a finebubble structure as shown in formulations 011, 012, 013 and 014. Suchfoams can be successfully produced in the presence or in the absence ofsilicone oils, as shown in formulation 011 and 016, despite thedefoaming effect of silicones. Moreover, formulations 012 and 014containing a combination of stearic acid with stearyl alcohol or behenylalcohol give rise to stable foams which did not collapse after 180 secat 36° C. Thus, it has been discovered that a combination of fattyalcohols and fatty acids has a synergistic effect and possesseseffective foaming properties in the case of oleaginous compositions toachieve a thermally stable breakable foam. Interestingly, cetyl andstearyl alcohol achieved the lowest average bubble size, whilst using acombination of the two led to a substantial reduction in viscosity ofthe pre foam formulation.

TABLE 8 Oleaginous compositions containing various Fatty Acids and FattyAlcohols 010 011 012 013 Formulation % w/w % w/w % w/w % w/w IngredientsHeavy mineral oil 60.00 60.00 60.00 60.00 Light Mineral oil 25.00 25.0025.00 25.00 Cyclomethicone 5.00 5.00 5.00 5.00 Myristyl alcohol 5.00 — —— Cetyl alcohol — 5.00 — — Stearyl alcohol — — 5.00 — Cetostearylalcohol — — — 5.00 Behenyl alcohol — — — — Isostearic acid — — — —Stearic acid 5.00 5.00 5.00 5.00 Total 100.00 100.00 100.00 100.00Propellant A46 12.00 12.00 12.00 12.00 Propellant AP-70 — — — — ResultsFoam quality Fair Good Good Good Collapse Time (sec) 10 30 >180 30 Foamdensity (g/mL) — 0.142 0.157 0.210 Bubble size micrometers — 60 74 137PFF Viscosity (cP) 107 22763 23866 107 Formulation 014 015 016 017Ingredients % w/w % w/w % w/w % w/w Heavy mineral oil 60.00 57.00 60.0060.00 Light Mineral oil 25.00 25.00 30.00 25.00 Cyclomethicone 5.00 5.00— 5.00 Myristyl alcohol — 3.00 — — Cetyl alcohol — — — — Stearyl alcohol— 5.00 5.00 5.00 Cetostearyl alcohol — — — — Behenyl alcohol 5.00 — — —Isostearic acid — — — 5.00 Stearic acid 5.00 5.00 5.00 — Total 100.00100.00 100.00 100.00 Propellant A46 12.00 — 12.00 12.00 Propellant AP-70— 8.00 — — Results Foam quality Good Good Good Fair Collapse Time(sec) >180 >180 >180 10 Foam density (g/mL) 0.139 0.082 0.100 — Bubblesize (micrometers) 139 — — — PFF Viscosity (cP) 5023 18987 — —

Example 9—Surfactant Free Hydrophobic Foam Formulations Containing FattyAlcohols, Fatty Acids and Waxes

Formulations, containing a combination of fatty acids, fatty alcoholsand waxes were prepared and checked for their foaming properties. Asnoted in Table 9a below, formulations 018 containing fatty alcohols andlow amounts of stearic acid did not give rise to quality foams butgenerated fairly good quality foam that very quickly collapsed.Surprisingly, the addition of hydrogenated castor oil and beeswax (informulation 019) both of which are solid waxes at room temperatureenhanced the foam quality and good quality foam that was stable at 36°C. was obtained. Furthermore, formulations containing waxes feel lessgreasy upon application on skin. Thus, it has been discovered thatwaxes, in combination with a fatty alcohol and a fatty acid, are usefulin producing a high quality foam without surfactants.

TABLE 9a Hydrophobic foam compositions containing waxes 018 019Formulations % w/w % w/w Ingredients Heavy mineral oil 63.00 59.50 Lightmineral oil 25.00 25.00 Cyclomethicone 5.00 5.00 Hydrogenated castor oil— 1.50 Beeswax — 2.00 Cetostearyl alcohol 2.50 2.50 Stearyl alcohol 1.501.50 Behenyl alcohol 1.00 1.00 Stearic acid 2.00 2.00 Total 100.00100.00 Propellant A46 12.00 12.00 Results Foam quality Fairly Good GoodCollapse Time (sec) 10 120 Foam density (g/mL) — 0.207 Bubble Sizemicrometers 155 79

Additional formulations were prepared, containing waxes alone and incombination with a fatty acid or a fatty alcohol and checked for theirfoaming properties. As described in Table 9b below, formulations 021,021 b and 022 containing beeswax alone or in combination withhydrogenated castor oil did not give rise to quality foams but merelygenerated bubbly liquids. Formulations 020 containing hydrogenatedcastor oil alone generated fairly good quality foam that collapsed after60 seconds. On the other hand the combination of beeswax, hydrogenatedcastor oil and fatty alcohol enhanced the foam quality and produced goodquality foam that were stable at 36° C. for more than 180 seconds, asshown in formulation 023. However, formulations 024 and 024b composed ofcombinations of beeswax, hydrogenated castor oil and fatty acid onlywithout fatty alcohol generated fairly good foam that quickly collapsed.This shows the importance of the presence of both fatty alcohols andwaxes in oleaginous foam compositions. Additionally, wax such ashydrogenated caster oil or beeswax can not only be used in place of afatty acid but it can be used to facilitate a lower level of fatty acidpresence without compromising the foam properties.

TABLE 9b Hydrophobic foam compositions containing waxes Formulations 020021 021b 022 023 024 024b Ingredients % w/w % w/w % w/w % w/w % w/w %w/w % w/w Heavy mineral oil 60.00 60.00 60.00 60.00 60.00 60.00 60.00Light mineral oil 25.00 25.00 30.00 25.00 25.00 25.00 25.00Cyclomethicone 5.00 5.00 — 5.00 5.00 5.00 5.00 Hydrogenated castor oil10.00 — — 5.00 2.50 2.50 5.00 Beeswax — 10.00 10.00 5.00 2.50 2.50 2.50Stearyl alcohol — — — — 5.00 — — Stearic acid — — — — — 5.00 5.00 Total100.00 100.00 100.00 100.00 100.00 100.00 100.00 Propellant A46 12.0012.00 12.00 12.00 12.00 12.00 12.00 Results Foam quality Fairly FairFair Fair Good Fairly Fairly Good Good Good Collapse Time (sec) 10 10 1010 >180 10 10

Example 10—Tetracycline Foam Formulations Containing DifferentHydrophobic Oils

Minocycline foam formulations were prepared containing soybean oil,octyldodecanol, Medium Chain Triglycerides (MCT) oil and coconut oil,which are other examples of hydrophobic oils. Parameters such as foamquality, collapse time and density were evaluated. As described in Table10, foams of good quality which did not collapse at 36° C. were obtainedin different compositions containing these hydrophobic oils. Coconutoil, which on its own is a semi solid paste like oil, was used incombination with liquid soybean oil.

TABLE 10 Foam formulation containing different hydrophobic oilsFormulations 199 216 232A 235 238 245 248 251 252 Heavy mineral oil55.89 58.82 — — 58.14 — — — — Light Mineral oil 25.00 25.00 25.00 —25.00 4.44 3.04 4.44 5.54 Cyclomethicone 5.00 5.00 5.00 5.00 5.00 5.005.00 5.00 5.00 MCT oil — — — 48.89 — — — — — Octyldodecanol — — — 12.00— — — — — Coconut oil — — 25.00 — — 23.60 25.00 21.60 25.00 PPG 15stearyl ether — — — 15.00 — — — — — Soybean oil — — 28.39 — — 50.0050.00 50.00 50.00 Lanolin — — — — — — — 2.0 2.00 Hydrogenated castor —1.50 2.00 2.00 1.50 2.00 2.00 2.00 2.00 oil Beeswax 1.87 2.50 2.50 2.002.00 2.00 2.00 2.00 Cholesterol — — — — — — 2.50 — — Myristyl alcohol3.00 — — — — 2.50 — 2.50 — Cetostearyl alcohol — 2.50 — 2.50 2.50 1.501.50 3.50 2.50 Stearyl alcohol 5.00 1.50 5.00 5.00 1.50 3.50 3.50 1.501.50 Behenyl alcohol — 0.70 1.00 1.00 1.00 1.10 1.10 1.10 1.10 Aerosil(SiO2) — — — — 0.25 0.25 0.25 0.25 0.25 Stearic acid 5.00 2.00 5.00 5.002.00 3.00 3.00 3.00 2.00 Minocycline HCl 1.11 1.11 1.11 1.11 1.11 1.111.11 1.11 1.11 Total 100 100 100 100 100 100 100 100 100 Propellant A46— 12.00 — 12.00 — 12.00 12.00 12.00 12.00 Propellant A70 8.00 — 8.00 —8.00 — — — — Results Foam Quality G E E G E E E G G Collapse Time at 36°C. >180 160 >180 150 >180 140 >180 >180 >180 (sec) Foam Density (g/mL)0.082 0.225 0.149 0.293 0.237 0.295 0.211 0.223 0.167

Comments: All the foams were of high quality and had a collapse time at36° C. in excess of 100 seconds, a foam density of less than 0.3 g/mland the formulations were able to withstand 4 freeze and thaw cycles andstill generate foam of high quality with a collapse time at 36° C. inexcess of 100 seconds. The above formulations, without the addition ofpropellant, are semi-solid gel-like homogeneous compositions where noseparation or sedimentation of the ingredients is observed.

Example 11—Tetracycline Foam Formulations Containing a Wax

The foaming properties of formulations containing mineral oil, aparaffin wax, a propellant and a tetracycline were studied. As shown inTable 11 below, formulations containing minocycline HCl, producedbreakable foams of quality having a collapse time of more than 1 minuteat 36° C., despite the absence of fatty alcohols and fatty acids.

TABLE 11 Tetracycline foam formulations containing a wax 053DFormulations % w/w Ingredients Heavy mineral oil 79.0 Paraffin 51-5320.0 Minocycline HCL 1.0 Total 100.0 Propellant AP-70 8.0 Results FoamQuality Excellent Shakability 2 Collapse Time at 36° C. (sec) >180

Example 12—Petrolatum Based Foamable Compositions

Foam formulations were prepared containing high amounts of Petrolatum,in combination with liquid oils, fatty alcohols and waxes, according tothe general manufacturing procedure described in Example 1. As describedin Table 12a, quality breakable foams were obtained in differentcompositions containing Petrolatum. The pre-foam formulations wereviscous semi-solid. Upon addition of propellant, the formulations wereshakable, indicating that the formulation within the aerosol canister isliquid.

TABLE 12a Oleaginous Formulations containing Petrolatum Formulations A1A2 A3 A8 White petrolatum 70.00 50.00 50.00 91.00 Grape seed oil — 15.00— — Jojoba oil 15.00 15.00 15.00 — Mineral oil 5.00 9.00 10.00 — Wheatgerm oil — — 15.00 — Paraffin wax 51-53 — 2.00 5.00 — Beeswax 1.00 1.00— 1.00 Cetostearyl alcohol 4.00 4.00 4.00 4.00 Hydrogenated castor oil3.00 2.00 — 3.00 Cyclomethicone 5-NF 1.00 1.00 — — Behenyl alcohol 1.001.00 1.00 1.00 Total 100 100 100 100 Propellant A70 10.00 10.00 10.0010.00 Results Foam Quality Excellent Excellent Excellent Excellent FoamDensity (g/mL) 0.159 0.154 0.175 0.226 Collapse time at 36° C.(sec) >180 >180 >180 >180 Mean Bubble size — — 150 — (micrometers)

In one or more embodiments, there is provided a foamable formulationcomprising Petrolatum, optionally a liquid oil, a fatty alcohol and awax, wherein the formulation generates quality breakable foam.

Foam formulations were also prepared without waxes, containing highamounts of Petrolatum, in combination with liquid oils and fattyalcohols, according to the general manufacturing procedure described inExample 1. As described in Table 12b, quality breakable foams wereobtained in different compositions containing Petrolatum without waxes.The pre-foam formulations were viscous semi-solid. Upon addition ofpropellant, the formulations were shakable, indicating that theformulation within the aerosol canister is liquid.

TABLE 12b Oleaginous Formulations containing Petrolatum Formulations A4A5 A6 A7 White petrolatum 50.00 70.00 70.00 75.00 Wheat germ oil — 10.00— — Jojoba oil — 5.00 — — Avocado oil 15.00 — — — Coconut oil 15.00 — —— Mineral oil 10.00 3.00 20.00 20.00 Shea butter 5.00 5.00 5.00 —Cetostearyl alcohol 4.00 4.00 4.00 4.00 Cyclomethicone 5-NF — 2.00 — —Behenyl alcohol 1.00 1.00 1.00 1.00 Total 100 100 100 100 Propellant A7010.00 10.00 10.00 10.00 Results Foam Quality Good Excellent ExcellentExcellent Foam Density (g/mL) 0.200 0.197 0.140 0.175 Collapse time at36° C. (sec) 175 >180 >180 >180

In one or more embodiments, there is provided a foamable formulationcomprising Petrolatum, and a fatty alcohol with optionally shea butter,wherein the formulation generates quality breakable foam. In one or moreembodiments, there is provided a foamable formulation comprisingPetrolatum, optionally a liquid oil, and a fatty alcohol with optionallyshea butter, wherein the formulation generates quality breakable foam.

Part C—Additional Properties of Tetracycline Compositions Example13—Stability of a Tetracycline Antibiotic in Surfactant Free HydrophobicFormulations

Tetracycline antibiotics are known to be very unstable active agentsthat are degraded by a wide range of commonly used pharmaceuticalexcipients. For example, it has been found that minocycline is degradedin a few days by different hydrophilic solvents (such as water,glycerin, sodium PCA, propylene glycol and polyethylene glycols), bywater dispersed polymers (such as xanthan gum, poloxamcrs, carbomcrs,mcthoccl, sodium CMC) and by surfactants (such as polysorbates, sorbitanesters, polyoxyalkyl esters and also lanolin-based surfactants). Thus,the achievement of a long term stable foamable formulation oftetracycline antibiotics described herein was a major challenge andrequired both extensive research and creativity.

The following example illustrates the physical stability of foams andthe chemical stability of minocycline HCl (“MCH”) in hydrophobicformulations, namely 238 and 244B as described in Tables 13a, 13b(i) and13b(ii). In an accelerated stability study, samples were stored at 40°C., and the concentrations of minocycline HCl were determined by HPLC.The stability test results following 2 months, 3 months and 6 months ofstorage are shown in Tables 13b(i) and 13b(ii).

TABLE 13a Composition of foam formulation incubated at 40° C. 238 244BFormulations % w/w % w/w Ingredients Heavy mineral oil 58.14 — Lightmineral oil 25.00 4.44 Cyclomethicone 5.00 5.00 Coconut oil — 23.60Soybean oil — 50.00 Lanolin — — Hydrogenated castor oil 1.50 2.00Beeswax 2.00 2.00 Cetostearyl alcohol 2.50 3.50 Stearyl alcohol 1.501.50 Behenyl alcohol 1.00 1.10 Myristyl alcohol — 2.50 Aerosil (SiO2)0.25 0.25 Stearic acid 2.00 3.00 Minocycline HCl 1.11 1.11 Total 100.00100.00 Propellant A46 — 12.00 Propellant AP-70 8.00 — Results Foamquality Excellent Excellent Collapse Time (sec) >180 >180 Foam density(glmL) 0.237 0.284

TABLE 13b(i) Chemical stability of foam compositions containingminocycline HCl Minocycline content (% of label claim) 2 months at 3months at 6 months at Formulation T0 40° C. 40° C. 40° C. 238 98.6 95.796.0 92.9 244B 98.7 97.1 93.8 90.3 NM = not measured

TABLE 13b(ii) Physical stability of foam compositions containingminocycline HCl Formu- 2 months 3 months 6 months lation Test T0 at 40°C. at 40° C. at 40° C. 238 Foam Quality Excellent Good Good GoodCollapse Time >180 >180 160 NM (sec) Foam Density 0.237 0.259 0.2890.263 (g/mL) 244B Foam Quality Excellent Good Good Good CollapseTime >180 >180 >180 NM (sec) Foam Density 0.284 0.256 NM 0.232 (g/mL) NM= not measured

Surprisingly, and despite the known instability of tetracyclineantibiotics, the accelerated stability results of both formulationsafter storage at 40° C. showed minimal degradation of the active agentin the formulations. The formulations disclosed herein thus show anextended accelerated stability for the tetracycline antibiotic and anoutstanding physical stability.

These results further illustrate the difficulty, complexity andunexpected and non obvious achievement of discovering surfactant freeand water free formulations that are chemically stable and are alsophysically stable over short term, medium term and or long term periods.Testing and identifying single substances that are compatible chemicallywith the active agent is not sufficient. Combining multiple substances,which on their own are compatible can lead to collectiveincompatibility. The discovery and knowledge of substances arechemically compatible does not presume physical stability of thecomposition or vice-versa. Running a compatibility study betweenindividual formulation components and the active agents does not ensurenor achieve physical stability. Discovering combinations of ingredientsthat can lead to a physically stable formulation in the absence ofsurfactant, is itself unexpected.

Example 14—Drug Comparison of the Stability of Minocycline in aHydrophobic Gel or Foam Formulation vs. A Reference Gel, on Contact withSkin

The objective of this study was to assess the degradation of minocyclinefollowing exposure to skin. Two samples were tested:

-   -   a. Hydrophobic minocycline formulation #244, containing 25%        light mineral oil, 5% cyclomethicone, 25% coconut oil, 28.5%        soybean oil (hydrophobic oils); 2% hydrogenated castor oil, 2.5%        beeswax (waxes); 5% stearyl alcohol, 1% behenyl alcohol (fatty        alcohols), 5% stearic acid (fatty acid and about 1% micronized        minocycline HCl    -   b. A reference minocycline gel, which comprised, amongst other        components, silicone and ST Elastomer 10, which were mixed prior        to application with an additional component that included water,        ethanol and propylene glycol.

Samples were applied to freshly retrieved pig's ear skin and stored on aPetri dish, with exposure to air and light for 6 hours at 35° C.; andthe concentrations of minocycline HCl and its 4-epi degradant weremonitored by liquid chromatography.

As shown in Table 14 below, the reference gel exhibited rapiddegradation of minocycline. After 6 hours of exposure the minocyclinecontent decreased by 34% and its 4-epi degradant content reached 19.4%,showing that the reference gel product fails to deliver the all theantibiotic amount to the skin in its active form.

By complete contrast, the “244”, surprisingly, and despite the knowninstability of minocycline, the skin stability results after 6h showed avery minimal degradation of the active agent: with the content of 4-epidegradant only reached 3.3% and no detectable decrease was observed inthe amount of minocycline. Therefore, the foam formulation has an activeprotective effect on the tetracycline antibiotic upon contact with theskin, and prevents its degradation on the target site of treatment overseveral hours.

In consequence of these observations, it is contemplated that thehydrophobic breakable composition protects the tetracycline antibioticfrom degradation; and therefore it is useful for the treatment of bodysites and surfaces which are moist and are exposed top air and/or light,without losing its potency following the application.

As known in the art of medicine, the duration of the effect of a drugrelates directly to its residence in the treatment site in its activeform; and therefore, it can be concluded that the current hydrophobicbreakable tetracycline composition will provide long-term treatment andfacilitate administration of the drug in lower frequency, in comparisonwith other forms of the same drug (if available).

TABLE 14 Skins stability results of compositions containing minocyclineHCl Reference 244 Silicone Gel Formulation Initial minocycline skinconcentration 96.90 92.20 Initial 4-epi degradant skin concentration2.60 0.80 Minocycline skin concentration after 6 h 64.00 93.70 at 35° C.4-epi degradant skin concentration after 19.40 3.30 6 h at 35° C.

Example 15: Safety of the Inactive Ingredients

All inactive ingredients used in the breakable hydrophobic tetracyclineformulations are intended for topical use and listed in the current FDAInactive Ingredient Database; and the concentrations used do not exceedthe maximum concentrations given in Database. As an example, Table 15lays out the acute dose effects of the formulation inactive ingredientsof formulation 244, indicating that all these ingredients can begenerally regarded as safe (GRAS).

TABLE 15 Acute dose effects of the formulation inactive ingredients offormulation 244 Ingredient Toxicity Cyclomethicone Oral LD50Rat: >24,134 mg/kg Coconut oil NA (edible) Soybean oil IV LD50 Rat: 16.5g/kg; IV LD50 Mouse: 22.1 g/kg Hydrogenated castor oil Oral LD50 Rat >10 g/kg Beeswax Oral LD50 Rat: >5,000 mg/kg Myristyl alcohol Oral LD50Rat: >10,000 mg/kg; Dermal LD50 Rabbit: >8,000 mg/kg Cetostearyl alcoholOral LD50 Rat: >10,000 mg/kg; Dermal LD50 Rabbit: >8,000 mg/kg Stearylalcohol Oral LD50 Rat: >10,000 mg/kg; Dermal LD50 Rabbit: >8,000 mg/kgBehenyl alcohol Oral LD50 Rat: 12,800 mg/kg Aerosil R 972 (modified OralLD50 Brachydanio rerio: >10,000 mg/kg silica) Stearic acid Oral LD50Rat: LD50 = 4640; Dermal LD50 Rabbit: >5000 mg/kg

Example 16: Eye Irritation Studies—HET CAM

The potential of compounds to cause irreversible or severe eyeirritation or corrosion may be detected by observing adverse changes,which occur in the chorioallantoic membrane (CAM) of the egg afterexposure to test chemicals (Luepke, N. P., Kemper, F. H. “The HET-CAMTest: An Alternative to the Draize Eye Test.” Fd Chem. Toxic. (1986) 24,495-496). Fertilized hen's eggs are rotated in an incubator for 9 days,after which any defective eggs are discarded. The shell around the aircell is removed and the inner membranes are extracted to reveal thechorionallantoic membrane. Test chemicals are added to the membrane andleft in contact for up to 5 minutes. The membrane is examined forvascular damage and the time taken for injury to occur is recorded.Irritancy is scored according to the speed at which damage occurs. Tovalidate the HET-CAM data, positive and negative controls and vehiclecontrol, are tested in parallel to the test item.

For each test item, mean scores of replicate eggs is determined.Irritation Score (IS) is interpreted as follows:

Irritation Score Irritation Classification   0-0.9 Non-Irritant   1-4.9Slight Irritant   5-8.9 Moderate Irritant  9-21 Severe Irritant

As can be seen in Table 16 using the in vitro irritation HET-CAM,FXFM244 with no dilution, demonstrated no signs of irritation.

TABLE 16 HET CAM studies of formulation 244 with 1% and 4% minocyclineTreatment Irritation Score Classification Negative Control 0 Nonirritant Positive Control 17.09 Severe Formulation 244B (1%) 0 Nonirritant Formulation 244A (4%) 0 Non irritant FXFM244 - Placebo 0 Nonirritant

In consequence of these observations, the hydrophobic breakabletetracycline composition is especially suitable for the treatment ofocular conditions, as well as other conditions that afflict sensitiveskin and mucosal membrane areas. Notably, the composition does notinclude any surfactants, which are known to cause irritation of the eyeand additional sensitive areas.

Eye conditions that can be contemplated based on the antimicrobialproperties of the tetracycline, plus the anti-inflammatory,anti-oxidative, anti-apoptosis and neuroprotective effects of certaintetracycline compound (such as minocycline and doxycycline) include, ina non limiting fashion can be categorized by their symptoms as follows:eye redness, eye pain or light sensitivity, blurred vision, loss ofvision, visual disturbances—floaters, flashing, distortion, halos, etc.,itching/burning, tearing/discharge, sensation of something in the eye,eyelid problems, double vision.

Examples of relevant conditions include macular degeneration,age-related macular degeneration, “dry” macular degeneration and “wet”macular degeneration, which are associated with photodamage andapoptosis, cataract, which is associated with apoptosis, glaucoma,open-angle glaucoma, closed-angle glaucoma (associated with opticalnerve death and apoptosis), retinopathy, proliferative diabeticretinopathy (apoptosis), macular Edema (inflammation), conjunctivitis,uveitis and trachoma (infection).

Non-limiting examples of ophthalmic conditions that can be treated by ahydrophobic breakable tetracycline composition of the present invention;or such conditions whose complications can be treated by saidcomposition; are provided herewith in their alphabetical order: allergy,blepharitis, cataract, central serous chorioretinopathy, color visionproblems, corneal abrasion, corneal edema, corneal ulcer,conjunctivitis, contact lens complications, dacryocystitis, blurreddistance vision, dry eye, eale's disease, episcleritis, eyelidectropion, eyelid entropion, eyelid cellulitis, eye strain, focusingspasm, glaucoma, acute glaucoma, iritis, keratoconus, lyme disease,macular degeneration, macular edema, macular hole, eye medicationtoxicity, myasthenia gravis, ocular cicatricial pemphigoid, ophthalmicmigraine, presbyopia, obstructed tear duct, optic neuritis, optic nervestroke, orbital fracture, orbital cellulitis, phlyctenulosis, pterygium,recurrent corneal erosion, retinal artery occlusion, retinal detachment,retinal tear, retinal vein occlusion, sarcoidosis, scleritis, sinusdisease, strabismus (ocular misalignment), subconjunctival hemorrhage,temporal arteritis, thyroid eye disease, trichiasis, eyelid tumor,twitching of eyelid (eyelid myokymia), uveitis, vitreous detachment andvitreous hemorrhage.

Example 17: In-Vitro Demonstration of Antibacterial Effects ofFormulation 244

In an in-vitro study it was revealed that formulation 244 with 1% and 4%minocycline inhibited the growth of Streptococcus pyogenes, Pseudomonasaeruginosa, Staphylococcus aureus, as well as a methicillin-resistantstrain of Staphylococcus aureus (MRSA), as shown in Table 11. Theformulation is also effective against Propionbacterium acnes, thecausative microorganism in acne. A reference antibiotic product, namelyFucidin Ointment (containing 2% fucidic acid) was effective only againstthe Streptococcus strains.

Notably, this effect was observed even though the tetracyclineantibiotic is suspended, and is not expected to be readily available formigration on the Petri dish as required for excreting its antimicrobialactivity.

TABLE 17 In Vitro Antibacterial Effect: Comparison between formulation244, Fucidin Ointment and Placebo - Diameter of inhibition (mm) 244 1%244 4% 244 Placebo Fucidin Inhibition Inhibition Inhibition InhibitionDiameter* Diameter* Diameter* Diameter* Staphylococcus aureus 6538 35,39, 36 mm >40, >40, >40 mm 13, 21, 20 mm >40, >40, >40 mm Pseudomonasaeruginosa 35, 36, 35 mm 40, 40, 40 mm 0, 0, 0 mm 11, 12, 16 mm 9027Staphylococcus aureus MRSA 32, 30, 21 mm >40, >40, >40 mm 17, 18, 20 mm40, 40, 38 mm 43300 Streptococcus pyogenes 19615 45, 38, 39 mm 38, 43,40 mm 12, 15, 11 mm 10, 12, 22 mm Propionbacterium acnes 32, 30, 35 mm32, 30, 35 mm NA NA *0 = Ineffective; ≥30 = Very Effective

In consequence of these observations, it is contemplated that thehydrophobic breakable tetracycline composition of the present inventionis useful in the treatment of any condition or disease, which can betreated with a gel or a foam, which includes a bacterial component asone of its etiological factors.

In consequence of these observations, the hydrophobic breakabletetracycline composition is especially suitable for the treatment of anycondition, which involves as a direct etiological factor or as asecondary complication an infection involving a microorganism which issusceptible to treatment with tetracycline.

Skin conditions that can be contemplated based on the antimicrobialproperties of the tetracycline, plus the anti-inflammatory,anti-oxidative and neuroprotective effects of certain tetracyclinecompound (such as minocycline and doxycycline) include, in a nonlimiting fashion include, for example: cellulitis, cutaneous abscess,erysipelas, erythrasma, folliculitis, furuncles and carbuncles,hidradenitis suppurativa, impetigo, ecthyma, lymphadenitis,lymphangitis, MRSA infections, necrotizing subcutaneous infection andstaphylococcal scalded skin syndrome.

Likewise, the composition of the present invention is suitable for thetreatment of any eye condition that involve bacterial infection, vaginalinfections, and any additional infections of target sites that may betreated by a gel or a foam.

The same compositions can be applicable in any case of a condition whichinvolves a secondary infection, such as atopic dermatitis and otheritching and xerotic conditions.

Example 18: Skin Delivery and Systemic Bioavailability of Minocycline

The transdermal penetration of minocycline was tested using the Franzcell in-vitro diffusion system. This system is commonly used to test thedelivery of drugs through the skin from semisolid topical dosage forms.Porcine skin was used according to the OECD Draft New Guideline 428, dueto its similar permeation characteristics to human skin. The followingexperimental parameters were employed:

-   -   Two formulations were tested: 244 1% and 244 4% (comprising 1%        and 4% Minocycline respectively).    -   Vertical Franz diffusion cells were used (PermeGear, 1.77 cm²        area, 14 ml receptor fluid).    -   6 cells were used to test the 4% formulation, 5 cells were used        to test the 1% formulation and. One cell was used as a “negative        control” (without any applied sample). Approximately 500 mg of        product was placed in each cell.    -   The receiving compartments were sampled at baseline and 3, 6, 9        and 24 hours following application. At the 24 hours time point        the skin was processed as follows:    -   Residues of materials were removed from the skin using filter        paper, followed by stripping the skin once using adhesive tape        “Scotch Magic® Tape”, 3M.    -   Sequential 19 tapes (9 and 10) should be transferred into two        separate vials with 3 mL extraction solution (“Stratum Corneum        1” and “Stratum Corneum 2”).    -   The circular skin area (1.77 cm²) was cut and transferred to a 3        mL extraction solution (Viable skin-VS samples) vial.

TABLE 18 In Vitro Skin Delivery: Formulation 244 (1% and 4%) FMFX244foam FMFX244 foam 1% (n = 5) 4% (n = 6) Minocycline Minocycline μg/cm²STD μg/cm² STD Stratum Corneum 1 7.77 4.32 33.63 20.41 Stratum Corneum 20.93 0.77 7.49 8.67 Total Stratum Corneum 8.70 4.97 41.12 16.89 ViableSkin 0.79 0.19 2.00 0.81 Total Intradermal Delivery 9.49 43.12 17.48Receiving Compartment 0.00 0.00

The following conclusions can be drawn from this experiment

1. Transdermal Delivery:

Following 24 hours of exposure the amount which was found in thereceptor cells was below the limit of quantitation (LOQ) of theanalytical method (LOQ=2 μg/mL). This result clearly demonstrates nosystemic absorption of the drug from the FMFX244 foam formulation. Itcan therefore be concluded that topical application of FMFX244 foamshould not involve any systemic adverse effects.

2. Intra-Dermal Delivery (Delivery into the Skin):

The total mean amount of Minocycline in the skin following 24 hours ofexposure was 9.5 μg/cm² for the 1% formulation and 43 μg/cm² for the 4%formulation. The weight of skin at the delivery area is about 100 mg,which implies that the concentration of Minocycline in the skinfollowing 24 hours of exposure is about 90 μg/gr of skin for the 1%formulation and about 430 μg/gr for the 4% formulation. According to theliterature, the minimum inhibitory concentration (MIC) for Minocyclineis less than 4 μg/mL, and therefore, it can be concluded that theconcentrations found in the skin are sufficient to treat bacterial skininfections.

Notably, this skin penetration profile was observed even though thetetracycline antibiotic is suspended, and is not expected to be readilyavailable for migration into the skin.

In consequence of these observations, the hydrophobic breakabletetracycline composition is especially suitable for the treatment of anyskin condition, which occurs in the skin.

Skin conditions that can be contemplated based on the antimicrobialproperties of the tetracycline, plus the anti-inflammatory,anti-oxidative, anti-apoptosis and neuroprotective effects of certaintetracycline compound (such as minocycline and doxycycline) include, ina non limiting fashion include, for example: abscess, acne, acne scars,acute febrile neutrophilic dermatosis, allergic contact dermatitis,alopecia, athlete's foot, atopic dermatitis, basal cell carcinoma,blisters, bromhidrosis, burn, calluses candidiasis, carbuncles,cellulitis, chicken pox, cholinergic urticaria, chronic effects ofsunlight, cold sores, cold urticaria, comedones, corns, cutaneousabscess, cutaneous larva migrans, cutaneous myiasis, dark spots,delusional parasitosis, dermatitis, dermographism, dermatophytoses, drugeruptions and reactions, dyshidrotic eczema, ecthyma, epidermoid cyst,erysipelas, erysipelas, erythrasma, exfoliative dermatitis, erythemamultiforme erythema nodosum, folliculitis, fungal nail infections,furuncles, genital herpes, granuloma annulare, head lice, hidradenitissuppurativa, hives, folliculitis, hirsutism, hyperhidrosis,hypohidrosis, ichthyosis, impetigo, ingrown nails, intertrigo, irritantcontact dermatitis, itching, jock itch, keratosis pilaris, lichensimplex chronicus, lichen planus, lichen sclerosus, lymphadenitis,lymphangitis, mastocytosis, measles, melanoma, miliaria, moles,molluscum contagiosum, MRSA, necrotizing subcutaneous infection,nummular dermatitis, oral herpes, panniculitis, parapsoriasisparonychia, photo-allergy, photo-damage, photo-irritation,photosensitivity, papules, perioral dermatitis, pimples, pityriasisrosea, pityriasis Lichenoides, pityriasis rosea, pityriasis rubrapilaris, poison ivy, pressure ulcers, pressure urticaria, pruritis,pseudofolliculitis barbae, psoriasis, PUPPP, pustules, pyogenicgranuloma, rash, ringworm, rosacea, roseola, rubella, scabies, sebaceouscyst, seborrheic dermatitis, seborrheic keratosis, shingles, skincancer, skin rash, staphylococcal scalded skin syndrome, stasisdermatitis, Stevens-Johnson syndrome, sunburn, tinea corporis, tineacruris, tinea pedis, tinea versicolor, toxic epidermal necrolysis,varicella zoster virus, vitamin D deficiency, water hives, xerosis,zoster.

Example 19: Ex-Vivo Studies of the Anti-Apoptosis Effects of Formulation244 with 1% and 4% Minocycline

UVB irradiation of the skin is known to decrease cell viability, totalantioxidant capacity, while increasing the levels of inflammation(pro-inflammatory cytokines secretion) and epidermal cell apoptosis.

Pre-Treatment with Formulation 244

Specimens of human skin in organ culture were treated topically withFormulation 244 (placebo, 1% and 4% minocycline) for 24 hours, thenirradiated with UVB (400 mJ/cm2) and incubated for additional 72 hours.Apoptosis activation was measured 24 h post-irradiation by measuring theextent of caspase 3 activity in epidermal sheets.

Table 19a and Table 19b demonstrate the effect of formulation 244 (withor without minocycline) on epidermal cell apoptosis and viabilityfollowing UVB irradiation of the skin organ culture. As shown in Table19a, apoptosis activation was significantly decreased by FXFM244 in adose-dependant manner.

Cell viability, as measured by the MTT assay 72 hours after irradiationwas increased, as shown in Table 19b. One set of mediators implicated inapoptosis belong to the asparate-specific cysteinyl proteases orcaspases. A member of this family, caspase-3 has been identified asbeing a key mediator of apoptosis of mammalian cells. In general terms,as caspase activation increases, a higher percentage of cell death willensue.

TABLE 19a Effect of Formulation 244 on apoptosis activation in skinorgan culture after UVB irradiation Caspase 3 activity (slope/min)Non-irradiated Irradiated Carrier 24 177 244 - 1% MCH 4 100 244 - 4% MCH3 69

TABLE 19b Effect of Formulation 244 on skin organ culture viabilityViability (RFU 540/590 nm) Non-irradiated Irradiated Carrier 6971.256207.5 244 - 1% MCH 7615.25 8862.25 244 - 4% MCH 8155.5 9015.5

Comments: It was observed that in the case of cells in contact with aplacebo formulation, irradiation causes a decrease in cell viability. Onthe other hand, in cells in contact with a formulation containingminocycline, higher cell viability was observed both before and afterirradiation compared to the placebo, which is a sign of cellregeneration. Therefore, the present formulation comprising minocyclineis able to prevent cell death in the case of irradiation and can evenstimulate or cause cell regeneration.

Treatment with Formulation 244 after UV Damage Induction

Specimens of human skin in organ culture were irradiated with UVB (400mJ/cm2) and incubated for additional 72 hours. Formulation 244 4% wasthen applied to the skin and apoptosis activation was measured 24 hpost-treatment by measuring the extent of caspase 3 activity inepidermal sheets.

As shown in Table 19c, Formulation 4% treatment resulted in about 60%decrease in epidermal cell apoptosis.

TABLE 19c Therapeutic effect of Formulation 244 (application postirradiation) Caspase 3 activity (slope/min) Control 118 244 - 4% MCH  46Conclusion

These results demonstrate that Formulation 244 has protective propertiesin the case of UVB-induced sun damage or any other condition associatedwith sunlight or other light (e.g., lazer) exposure. It may therefore beable to reduce skin photodamage and photoaging, and more generally toreduce oxidative stress and inflammation in skin pathologies which areknown to be accompanied by apoptotic cell death.

Notably, this skin penetration profile was observed even though thetetracycline antibiotic is suspended, and is not expected to be readilyavailable for migration into the tissue and providing the desirableanti-apoptotic effect.

In consequence of these observations, the hydrophobic breakabletetracycline composition is especially suitable for the treatment of anycondition, which includes apoptosis as one of its etiological factors.

Example 20—Compatibility Study

Procedure: Minocycline hydrochloride (“MCH”) was incubated as asuspension with various excipients at 25° C. and 40° C. for maximum ofsixty days or to the point where degradation was suspected. The ratiobetween MCH and the tested excipient is detailed below. Visualinspection was the major criterion for indication of compatibility. Thecolor of intact MCH suspension is pale yellow; and any change of color(e.g., to dark orange, red, green, brown and black) indicates oxidationor degradation.

Hydrophilic solvents were tested for compatibility with MCH at a ratioof MCH:excipient of 1:250. dimethyl isosorbide, glycerin, ethanol,propylene glycol, butylene glycol, PEG 200, hexylene glycol, PEG 400,dimethyl sulfoxide and diethylene glycol monoethyl ether were found tobe incompatible with MCH.

Oily emollients and waxes were tested for compatibility with MCH at aratio of MCH:excipient of 1:250 for Oily emollients and 1:50 for waxes.Hydrogenated castor oil, castor oil, cocoglycerides, disopropyl adipate,mineral oil, coconut oil, beeswax, MCT oil, cyclomethicone, isododecane,cetearyl octanoate, gelled mineral oil, isopropyl myristate, PPG 15stearyl ether, mineral oil heavy, octyl dodecanol, white petrolatum,petrolatum, paraffin 51-53, paraffin 58-62, calendula oil, shea butter,grape seed oil, almond oil, jojoba oil, avocado oil, peanut oil, wheatgerm oil and hard fat were found to be compatible with MCH. Pomegranateseed oil was found to be incompatible with MCH.

The compatibility of MCH with hydrophobic surfactant was testedfollowing solubilization of the surfactant in mineral oil (mineral oilwas previously shown to be compatible with MCH). Surfactants were testedfor compatibility with MCH at a ratio of MCH:excipient of 1:50. PEG 150distearate, laureth 4, PEG 40 hydrogenated castor oil, PEG 75 lanolin,glucam P20 distearate, PEG 100 stearate, glyceryl monostearate, PEG 40stearate, montanov S (cocoyl alcohol (and) C12-20 alkyl glucoside)),alkyl lactate, benton gel, SPAN 60, sorbitan sesquistearate, SPAN 40,SPAN 80, Tween 20, Tween 60, ceteth 2, sucrose stearic acid estersD1813, ceteareth 20, steareth 2/steareth 21, methyl glucosesesquistearate, Oleth 20, and PPG 20 methyl glucose ether were found tobe incompatible with MCH. Sucrose stearic acid esters D1803, sucrosestearic acid esters D1807 and sucrose stearic acid esters D1811 werefound to be compatible with MCH; however, not all of them dissolved inoil (e.g. 1811, 1813).

Foam adjuvants were tested for compatibility with MCH at a ratio ofMCH:excipient of 1:50. Isostearyl alcohol, behenyl alcohol, stearylalcohol, cetyl alcohol, oleyl alcohol, myristyl alcohol, cetostearylalcohol, palmitic acid, stearic acid and oleic acid were found to becompatible with MCH. Isostearic acid was not compatible with MCH.

Additives were tested for compatibility with MCH at a ratio ofMCH:excipient of 1:50. Aerosil and Menthol were found to be compatiblewith MCH. Titanium dioxide and Ethocel were not compatible with MCH.

Additives were tested for compatibility with MCH. Minimal quantities ofwater (100 μL) were added to MCH, suspended in excipients that haddemonstrated compatibility to examine whether water can enhanceoxidation/degradation in the absence or presence of antioxidant. Inparallel, antioxidants were added to the MCH suspensions comprisingwater. Antioxidants were also added to excipients which were found to benon compatible with MCH. Addition of water caused prompt degradation ofMCH. Addition of the antioxidants alpha-tocopherol, BHA/BHT and propylgallate did not prevent MCH degradation. Compatible excipients becameincompatible in the presence of water. Addition of antioxidants did notalter this result.

Example 21—Color and Pigmentation Study Part A—Color Change

Samples of formulations 238 and 216 with 1% minocycline were incubatedduring 3 months at 25° C., 30° C. and 40° C. Following this period thefoam product was actuated and the change in color was observed. Minimalto no change was observed following 3 months storage at all threetemperatures.

Part B—Pigmentation

A large amount of MCH 244 4% was actuated on human skin to observewhether any skin pigmentation occurs. Minimal to no skin pigmentationfollowing rubbing the foam onto the skin was noticed, when observedafter about 30 seconds.

What is claimed is:
 1. A waterless foam composition comprising: aminocycline; a retinoid; and a foamable carrier, the carrier comprising:a) at least one hydrophobic oil; and b) an agent comprising (i) at leastone fatty alcohol and at least one wax; (ii) at least one fatty acid andat least one wax; (iii) at least one fatty alcohol, at least one fattyacid, and at least one wax; (iv) a wax comprising a hydrogenated oil; or(v) a combination of two or more waxes; wherein the composition does notcontain one or more minocycline incompatible substance selected from thegroup consisting of dimethyl sulfoxide (DMSO), dimethylformamide (DMF),acetonitrile, acetone, methyl ethyl ketone, 1,4-dioxane, tetrahydrofuran(THF), N-methylpyrrolidone, pyridine, piperidine, N-methyl-2-pyrrolidoneand 1-methyl-2-pyrrolidinone), azone (1-dodecylazacycloheptan-2-one),dimethyl isosorbide, glycerin, ethanol, propylene glycol, butyleneglycol, PEG 200, hexylene glycol, PEG 400, diethylene glycol monoethylether, pomegranate seed oil, isostearic acid, and ethylcellulose;wherein the composition does not contain a surfactant; and wherein thecomposition does not contain a polyol.
 2. The composition of claim 1,wherein the at least one hydrophobic oil comprises a mineral oil, acocoglyceride, a silicone oil, a liquid paraffin, a caprylic/caprictriglyceride, a coconut oil, a soybean oil, a cyclomethicone, disopropyladipate isododecane, cetearyl octanoate, a gelled mineral oil, isopropylmyristate, PPG 15 stearyl ether, octyl dodecanol, a petrolatum, acalendula oil, a grape seed oil, an almond oil, a jojoba oil, an avocadooil, a peanut oil, a wheat germ oil, or a mixture of any two or morethereof.
 3. The composition of claim 1, wherein at least one or both ofthe fatty alcohol or the fatty acid has at least 12 carbon atoms in itscarbon backbone.
 4. The composition of claim 1, wherein the agentcomprises at least one fatty alcohol, at least one fatty acid, and atleast one wax, wherein the at least one wax comprises a beeswax, ahydrogenated oil, or both.
 5. The composition of claim 1, wherein thecomposition contains (1) less than 0.4% by weight of a protic solvent, apolar aprotic solvent, and a silicone thickening agent or (2) less than0.4% by weight of a polymeric gelling agent, a short chain alcohol, anda silicone thickening agent.
 6. The composition of claim 1, wherein thefoamable carrier comprises: a) 45% to 55% by weight of a soybean oil; b)21.2% to 26% by weight of a coconut oil; c) 4.5% to 5.5% by weight of acyclomethicone; d) 0.85% to 4.8% by weight of a light mineral oil; e)3.2% to 3.9% by weight of cetostearyl alcohol; f) 2.7% to 3.3% by weightof stearic acid; g) 2.3% to 2.8% by weight of myristyl alcohol; h)hydrogenated castor oil; i) beeswax; j) 1.4% to 1.7% by weight ofstearyl alcohol; and k) 1% to 1.2% by weight of behenyl alcohol.
 7. Thecomposition of claim 6, wherein hydrogenated castor oil is present atabout 0.1% to about 1% of the composition or at about 1% to about 5% ofthe composition.
 8. The composition of claim 6, wherein beeswax ispresent at about 1% to about 10% of the composition.
 9. The compositionof claim 1, wherein the minocycline is present at about 1% to about 10%of the composition.
 10. The composition of claim 1, wherein theminocycline is present at about 3% of the composition.
 11. Thecomposition of claim 1, wherein the retinoid is adapalene.
 12. Thecomposition of claim 1, wherein the composition is free of or comprisesless than 10% petrolatum by weight of the composition.
 13. Thecomposition of claim 1, wherein the at least one hydrophobic oil isabout 60% to about 99% by weight of the composition.
 14. The compositionof claim 1, wherein the foam composition is produced with a liquefied orcompressed gas propellant.
 15. The composition of claim 1, comprising ahydrocarbon oil, an ester oil, an ester of a dicarboxylic acid, atriglyceride oil, an unsaturated or polyunsaturated oil, an essentialoil, a canola oil, a castor oil, a corn oil, a cotton oil, a cottonseedoil, glycerol, an olive oil, a palm oil, a dimethicone, a fattyacid-modified silicone oil, or a mixture of any two or more thereof. 16.A method of treating or alleviating the symptoms of a dermatologicaldisorder, comprising: applying to a target area the composition ofclaim
 1. 17. The method of claim 16, wherein the composition isadministered at least once daily.
 18. The method of claim 16, whereinthe composition is administered at least once daily and the minocyclineis present at about 3% of the composition.
 19. The method of claim 16,wherein the disorder is acne.
 20. A waterless composition comprising: acarrier; a retinoid; and 1% to 10% by weight of the composition of aminocycline, wherein the carrier comprises: a) at least one hydrophobicoil; and b) an agent comprising (i) at least one fatty alcohol and atleast one wax; (ii) at least one fatty acid and at least one wax; (iii)at least one fatty alcohol, at least one fatty acid, and at least onewax; (iv) a wax comprising a hydrogenated oil; or (v) a combination oftwo or more waxes; wherein the composition does not contain asurfactant; wherein the composition does not contain a polyol.
 21. Thecomposition of claim 20, wherein the minocycline is minocyclinehydrochloride and is present at an amount of about 3% by weight of thecomposition.
 22. The composition of claim 20, wherein the agentcomprises at least one fatty alcohol, at least one fatty acid, and atleast one wax.
 23. The composition of claim 20, wherein the compositionis a foam composition, and wherein the foam composition is produced uponaddition of a liquefied or compressed gas propellant to the carrier. 24.The composition of claim 20, wherein the retinoid is adapalene.
 25. Thecomposition of claim 20, wherein the carrier comprises: a) 45% to 55% byweight of a soybean oil; b) 21.2% to 26% by weight of a coconut oil; c)4.5% to 5.5% by weight of a cyclomethicone; d) 0.85% to 4.8% by weightof a light mineral oil; e) 3.2% to 3.9% by weight of cetostearylalcohol; f) 2.7% to 3.3% by weight of stearic acid; g) 2.3% to 2.8% byweight of myristyl alcohol; h) hydrogenated castor oil; i) beeswax; j)1.4% to 1.7% by weight of stearyl alcohol; and k) 1% to 1.2% by weightof behenyl alcohol.
 26. The composition of claim 25, whereinhydrogenated castor oil is present at about 0.1% to about 1% of thecomposition or at about 1% to about 5% of the composition.
 27. Thecomposition of claim 25, wherein beeswax is present at about 1% to about10% of the composition.
 28. A method of treating or alleviating thesymptoms of a dermatological disorder, comprising: applying to a targetarea the composition of claim
 20. 29. The method of claim 28, whereinthe disorder is acne.
 30. A waterless composition comprising: a carrier;a retinoid; and 1% to 10% by weight of the composition of a tetracyclineantibiotic, wherein the carrier comprises: a) at least one hydrophobicoil; and b) an agent comprising (i) at least one fatty alcohol and atleast one wax; (ii) at least one fatty acid and at least one wax; (iii)at least one fatty alcohol, at least one fatty acid, and at least onewax; (iv) a wax comprising a hydrogenated oil; or (v) a combination oftwo or more waxes; wherein the composition does not contain asurfactant; wherein the composition does not contain a polyol.